About ERBB4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERBB4 c.2371A>G, p.(Thr791Ala)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is present at extremely low frequency in population databases. gnomAD v2.1 reports 3/251,416 alleles (AF=0.00119%) and gnomAD v4.1 reports 24/1,614,034 alleles (AF=0.00149%), both well below the 0.1% threshold. No homozygotes are observed. gnomAD-Canada v1.0 reports the variant as absent.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, consistent with a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00).
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
24 / 1,614,034 alleles
gnomAD v4.1: 24 / 1,614,034 alleles. Recorded AF 1.48696e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19324e-05; MAF= 0.00119%, 3/251416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.63764e-05; MAF= 0.00264%, 3/113738 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERBB4, a receptor tyrosine kinase, is altered at low to moderate frequencies in various cancer types, most frequently in melanoma and lung cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005235.2:c.2371A>G (p.Thr791Ala) is a missense variant in exon 20 of ERBB4. It is present at extremely low frequency in population databases (gnomAD v2.1: 3/251,416 alleles, AF=0.00119%; gnomAD v4.1: 24/1,614,034 alleles, AF=0.00149%) with no homozygotes observed, meeting PM2 at supporting strength.
Multiple computational predictors support a benign interpretation: REVEL score of 0.321 is below the pathogenic threshold, BayesDel score of -0.090 is in the benign range, and SpliceAI predicts no splice impact (max delta = 0.00). BP4 is met at supporting strength.
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories (LabCorp, Ambry Genetics), each with criteria provided as a single submitter. No expert panel review has been performed.
No functional studies, segregation data, de novo observations, case-control studies, or family co-segregation data are available for this variant. The variant lies within the ERBB4 kinase domain but is not located in a recognized mutational hotspot.
Applying the generic ACMG/AMP 2015 final classification rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in an overall classification of Uncertain Significance. The evidence is balanced and insufficient to classify this variant as either likely pathogenic or likely benign.
No criteria match.
Met · 2
PM2 SupportingThis variant is present at extremely low frequency in population databases. gnomAD v2.1 reports 3/251,416 alleles (AF=0.00119%) and gnomAD v4.1 reports 24/1,614,034 alleles (AF=0.00149%), both well below the 0.1% threshold. No homozygotes are observed. gnomAD-Canada v1.0 reports the variant as absent. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00119% (3/251
- 416 alleles
- 0 hom)
- gnomAD v4.1: AF=0.00149% (24/1
- 614
- 034 alleles
- grpmax FAF v2.1=7.01e-06
- v4.1=3.471e-05
- gnomAD-Canada: absent.
Sources
BP4 SupportingMultiple lines of computational evidence support a benign effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, consistent with a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (below 0.5 pathogenic threshold)
- BayesDel: -0.0903471 (benign range)
- SpliceAI: max delta=0.00 (no predicted splice alteration).
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternate nucleotide change resulting in the same amino acid substitution (p.Thr791Ala) has been reported as pathogenic. No ClinVar entry or publication identifies a different nucleotide change at codon 791 producing Thr791Ala. Details ▾Hide ▴
Evidence considered
- ClinVar contains only NM_005235.3:c.2371A>G (p.Thr791Ala) classified as VUS.
Still missing
- No alternate nucleotide change at codon 791 has been characterized.
Sources
PS2 No de novo occurrence of NM_005235.2:c.2371A>G with confirmed paternity and maternity has been reported in the literature or variant databases. Details ▾Hide ▴
Evidence considered
- Systematic literature search and database review identified no de novo reports for this variant.
Still missing
- No trio-based or de novo studies for this variant were identified.
PS3 No well-established functional studies have been performed to assess the damaging effect of p.Thr791Ala. OncoKB reports no variant-specific reviewed functional evidence, and COSMIC contains no entry for this variant. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data. COSMIC: not found. Exploratory targeted search (PMID:19668190
- PMID:20581867) found no functional characterization of p.Thr791Ala.
Still missing
- No in vitro or in vivo functional studies of p.Thr791Ala are available.
Sources
PS4 No case-control studies have compared the prevalence of NM_005235.2:c.2371A>G in affected individuals versus general population controls. The variant is present at very low frequency in gnomAD (AF ~0.001%) and has not been enriched in any disease cohort. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 3/251
- 416 alleles (AF=0.00119%)
- gnomAD v4.1: 24/1
- 614
- 034 alleles (AF=0.00149%). No disease-specific cohort data available.
Still missing
- No case-control or cohort enrichment data for this variant.
Sources
PM1 Although p.Thr791 resides within the ERBB4 protein kinase domain (residues 712–989), the variant is not located in a statistically significant mutational hotspot. Cancer Hotspots database confirms the residue is not significant and the exact variant is not listed. No domain-level constraint metrics (missense Z-score, regional constraint) have been evaluated to demonstrate intolerance of benign missense variation at this position. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue_significant=false
- exact_variant_listed=no. UniProt: kinase domain residues 712–989.
Still missing
- No evidence that codon 791 is a mutational hotspot or that the kinase domain is depleted of benign missense variation in population databases.
Sources
PM6 No presumed de novo occurrence (without confirmation of paternity and maternity) has been reported for NM_005235.2:c.2371A>G in the literature or variant databases. Details ▾Hide ▴
Evidence considered
- Systematic search identified no presumed de novo reports for this variant.
Still missing
- No de novo observations
- with or without parental confirmation.
PP1 No co-segregation data are available. No multiplex pedigrees demonstrating co-segregation of NM_005235.2:c.2371A>G with a consistent phenotype have been reported. Details ▾Hide ▴
Evidence considered
- No family-based linkage or co-segregation studies identified.
Still missing
- No segregation or family studies available.
PP2 There is insufficient evidence that ERBB4 meets the PP2 criteria: a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. No gene-level missense constraint data (e.g., missense Z-score) have been evaluated to support this criterion. Details ▾Hide ▴
Evidence considered
- No evidence demonstrating that ERBB4 missense variants are constrained or that benign missense variation is depleted.
Still missing
- No constraint metrics (missense Z-score
- LOEUF
- regional constraint) evaluated for ERBB4.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, supporting a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (benign-leaning)
- BayesDel: -0.0903471 (benign)
- SpliceAI: max delta=0.00 (no predicted splice impact).
Sources
PP4 No phenotypic data are available for the individual(s) carrying this variant. Without patient phenotype or family history information, specificity for an ERBB4-associated disorder cannot be assessed. Details ▾Hide ▴
Evidence considered
- No patient phenotype
- clinical history
- or family history data available in the case record.
Still missing
- No phenotypic or clinical data provided.
PP5 No reputable source has classified this variant as pathogenic. ClinVar reports this variant as Uncertain significance based on submissions from two clinical laboratories (LabCorp, Ambry Genetics), each with criteria provided, single submitter. No expert panel review has been performed. Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3063763: classification=Uncertain significance
- review_status=criteria provided
- single submitter
- 2 clinical laboratories
- 0 expert panel submissions.
Sources
BA1 The maximum population allele frequency for NM_005235.2:c.2371A>G is 0.00801% in the African/African American subpopulation (gnomAD v4.1), far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- Max sub-population AF: 8.00747e-05 (0.00801%) in gnomAD v4.1 African/African American population.
Sources
BS1 The maximum population allele frequency for NM_005235.2:c.2371A>G is 0.00801% (gnomAD v4.1 African/African American), well below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
- Max sub-population AF: 0.00801% in gnomAD v4.1
- gnomAD v2.1 max sub-pop AF: 0.00264% in European (non-Finnish).
Sources
BS2 No homozygous individuals have been observed in gnomAD (v2.1 or v4.1). No observation of this variant in trans with a known pathogenic variant in a dominant disorder has been documented. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes. No trans observations reported.
Still missing
- No homozygous or trans observations available.
Sources
BS3 No well-established functional studies demonstrating a neutral or benign effect of p.Thr791Ala on protein function have been identified. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional assay data available for p.Thr791Ala.
Still missing
- No functional characterization of this variant has been performed.
BS4 No segregation data are available to evaluate lack of segregation in affected family members. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
- No family-based segregation or co-occurrence data available.
Still missing
- No segregation analysis has been performed for this variant.
BP1 ERBB4 is not established as a gene where only truncating variants cause disease. Missense variants in ERBB4 have been implicated in amyotrophic lateral sclerosis (PMID:40469844), and the gene's disease mechanism is not restricted to loss-of-function truncations alone. Details ▾Hide ▴
Evidence considered
- Literature review identifies both missense and splice region variants in ERBB4 associated with ALS
- disease mechanism not limited to truncating variants.
Sources
pvs1_gene_context
BP2 No observation of NM_005235.2:c.2371A>G in trans with a pathogenic variant in a gene for a fully penetrant dominant disorder, nor in cis with a pathogenic variant in any inheritance pattern, has been reported. Details ▾Hide ▴
Evidence considered
- No trans or cis observations with a pathogenic variant reported in the literature or databases.
Still missing
- No phase information with pathogenic variants available.
BP5 No case has been reported in which NM_005235.2:c.2371A>G is found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No reports of this variant co-occurring with a confirmed pathogenic variant in a different gene that explains the phenotype.
Still missing
- No alternate molecular diagnosis data available.
BP6 No reputable source has classified this variant as benign. ClinVar reports this variant as Uncertain significance (2 clinical laboratories, single submitter each). Details ▾Hide ▴
Evidence considered
- ClinVar VariationID 3063763: classification=Uncertain significance
- no benign classification from any submitter.
Sources
PS5 No established pathogenic variant at codon 791 with a different amino acid substitution has been identified. No ClinVar entries or publications describe a pathogenic missense change at this residue. Details ▾Hide ▴
Evidence considered
- ClinVar review identifies no pathogenic variant at codon 791. PM5 candidate harvesting found no same-residue comparator variants.
Still missing
- No pathogenic comparator at codon 791 available.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, exon deletion). NM_005235.2:c.2371A>G is a missense variant (p.Thr791Ala) and does not meet the allele-type requirement for PVS1 application. Details ▾Hide ▴
Evidence considered
- Missense variant does not fall into any PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped: no recessive disease has been firmly linked to biallelic ERBB4 mutations, and no trans observation with a pathogenic variant has been reported. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped: variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at codon 791 with a different amino acid change has been identified. PM5 candidate harvesting returned no comparators, and the criterion cannot be applied. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection found 0 same-residue comparator variants in ClinVar or literature.
Sources
pm5_candidates
BP3 N/ASkipped: variant is a substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 is specific to synonymous variants with no predicted splice impact. NM_005235.2:c.2371A>G is a missense variant (p.Thr791Ala) and does not qualify for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- not synonymous.
Identifiers
- Gene
- ERBB4
- Transcript
- NM_005235.2
- Coding (HGVS c.)
- NM_005235.2:c.2371A>G
- Protein (HGVS p.)
- NP_005226.1:p.(Thr791Ala)
- GRCh38
- chr2:211562019 T>C
- GRCh37
- chr2:212426744 T>C
- ClinVar
- 3063763
Gene diagram
Every interpreted variant in ERBB4, mapped onto the exon structure of NM_005235.2. Select a row to find it on the plot.
ERBB4NM_005235.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ERBB4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
24 / 1,614,034 alleles
AF 1.49e-05 · 0 homozygotes · FAF 3.47e-05
gnomAD v2.1
3 / 251,416 alleles
AF 1.19e-05 · 0 homozygotes · FAF 7.01e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 24 / 1,614,034 alleles · 0 hom · FAF 3.5e-05
| African/African American6 / 74,930 | 8e-05 |
| European (non-Finnish)18 / 1,180,036 | 1.5e-05 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 1.2e-05 · 3 / 251,416 alleles · 0 hom · FAF 7e-06
| European (non-Finnish)3 / 113,738 | 2.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.48696e-05; MAF= 0.00149%, 24/1614034 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.00747e-05; MAF= 0.00801%, 6/74930 alleles, homozygotes = 0); grpmax FAF= 3.471e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19324e-05; MAF= 0.00119%, 3/251416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.63764e-05; MAF= 0.00264%, 3/113738 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.321
- BayesDel
- -0.090
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, consistent with a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (below 0.5 pathogenic threshold)
- BayesDel: -0.0903471 (benign range)
- SpliceAI: max delta=0.00 (no predicted splice alteration).
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.321 (below the pathogenic threshold of 0.5), BayesDel score is -0.090 (negative, supporting a benign interpretation), and SpliceAI predicts no splice impact (max delta score = 0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.321 (benign-leaning)
- BayesDel: -0.0903471 (benign)
- SpliceAI: max delta=0.00 (no predicted splice impact).
Sources
BP7 N/ABP7 is specific to synonymous variants with no predicted splice impact. NM_005235.2:c.2371A>G is a missense variant (p.Thr791Ala) and does not qualify for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant type is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.321. BayesDel score = -0.0903471.
12 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.No paper-specific finding is recorded.
-
PMID 23652378 ↗A framework to start the debate on neonatal screening policies in the EU: an Expert Opinion Document.Cornel MC et al. · 2014No paper-specific finding is recorded.
-
PMID 25626707 ↗Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes.Howard HC et al. · 2015No paper-specific finding is recorded.
-
PMID 25730230 ↗Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine.Edwards JG et al. · 2015No paper-specific finding is recorded.
-
PMID 23169492 ↗The perspective from EASAC and FEAM on direct-to-consumer genetic testing for health-related purposes.Fears R et al. · 2013No paper-specific finding is recorded.
-
PMID 24121147 ↗Appropriateness of newborn screening for α1-antitrypsin deficiency.Teckman J et al. · 2014No paper-specific finding is recorded.
-
PMID 22947299 ↗Specific guidelines for assessing and improving the methodological quality of economic evaluations of newborn screening.Langer A et al. · 2012No paper-specific finding is recorded.
-
PMID 23037933 ↗Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children.Therrell BL et al. · 2013No paper-specific finding is recorded.
-
PMID 23881473 ↗Newborn screening: education, consent, and the residual blood spot. The position of the national society of genetic counselors.Blout C et al. · 2014No paper-specific finding is recorded.
-
PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].Skirton H et al. · 2014No paper-specific finding is recorded.
-
PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Botkin JR et al. · 2014No paper-specific finding is recorded.
-
PMID 31022120 ↗ACOG Committee Opinion No. 778 Summary: Newborn Screening and the Role of the Obstetrician-Gynecologist.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
24 / 1,614,034 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3063763/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-212426744-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-211562019-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005235.2%3Ac.2371…
- OncoKB ↗www.oncokb.org/gene/ERBB4/T791A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERBB4+c.2371A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.48696e-05; MAF= 0.00149%, 24/1614034 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.00747e-05; MAF= 0.00801%, 6/74930 alleles, homozygotes = 0); grpmax FAF= 3.471e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.19324e-05; MAF= 0.00119%, 3/251416 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.63764e-05; MAF= 0.00264%, 3/113738 alleles, homozygotes = 0); grpmax FAF= 7.01e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3063763)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.321. BayesDel score = -0.0903471.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERBB4, a receptor tyrosine kinase, is altered at low to moderate frequencies in various cancer types, most frequently in melanoma and lung cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.