About ALK
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ALK c.4033G>A, p.(Gly1345Arg)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_004304.4:c.4033G>A is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (overall AF = 1.86 × 10⁻⁶, 3/1,613,830 alleles; highest subpopulation frequency = 2.54 × 10⁻⁶ in European non-Finnish; grpmax FAF = 6.8 × 10⁻⁷). This frequency is well below the non-VCEP PM2 supporting threshold of <0.1%.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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; combination = 1 supporting, 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
3 / 1,613,830 alleles
gnomAD v4.1: 3 / 1,613,830 alleles. Recorded AF 1.85893e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI score
0.200 maximum delta
Recorded SpliceAI maximum delta score: 0.200. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 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. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma
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.
27 criteria with recorded statuses: 1 met · 10 not met · 11 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004304.4:c.4033G>A (p.Gly1345Arg) is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF 1.86 × 10⁻⁶, 3/1,613,830 alleles), meeting PM2 at supporting strength.
The variant is a missense substitution not located in a statistically significant mutational hotspot; PM1 is not met.
In silico predictions are conflicting: REVEL score 0.786 supports a deleterious effect, but BayesDel score 0.144 is in the benign range and SpliceAI max delta 0.20 is borderline. PP3 is not met, and BP4 is not met.
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory, SCV002134937); no reputable source classifies it as pathogenic or benign. PP5 and BP6 are not met.
No variant-specific functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), or case-control data (PS4) were identified. PVS1 is not applicable as this is a missense variant outside canonical null-variant categories.
With only PM2_Supporting met, the variant does not reach a Likely Pathogenic threshold (requiring at least 2 Supporting criteria or 1 Moderate + 1 Supporting under generic ACMG/AMP rules) nor a Likely Benign threshold. The variant remains a Variant of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingNM_004304.4:c.4033G>A is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (overall AF = 1.86 × 10⁻⁶, 3/1,613,830 alleles; highest subpopulation frequency = 2.54 × 10⁻⁶ in European non-Finnish; grpmax FAF = 6.8 × 10⁻⁷). This frequency is well below the non-VCEP PM2 supporting threshold of <0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: AF 1.86e-06 (0.00019%)
- 3 alleles total in NFE subpopulation
- 0 homozygotes
- grpmax FAF 6.8e-07.
Sources
Not met · 10 · evaluated, threshold not reached
PS3 No variant-specific well-established in vitro or in vivo functional studies were identified. OncoKB reports Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. SpliceAI delta score of 0.20 does not independently constitute functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect with no variant-specific functional evidence. SpliceAI max delta 0.20
- not meeting threshold for functional splice impact.
Still missing
- No variant-specific functional assays (e.g.
- kinase activity
- transformation assays) available.
Sources
PM1 The variant is not located in a statistically significant mutational hotspot. Although p.Gly1345 resides in the C-terminal region of the ALK tyrosine kinase domain, no functional domain-level PM1 assignment has been established by a CSPEC/VCEP, and hotspots analysis did not identify this residue as significant. Details ▾Hide ▴
Evidence considered
- Hotspots analysis: residue not significant
- exact variant not listed in hotspot database. No CSPEC/VCEP domain-level PM1 rule available.
Still missing
- No VCEP-defined functional domain annotation for PM1 in ALK.
PP3 In silico predictions are conflicting and do not provide multiple concordant lines of computational evidence for a deleterious effect. REVEL score 0.786 supports pathogenicity, but BayesDel score 0.144 falls in the benign range, and SpliceAI max delta 0.20 is at the threshold of significance (DL 0.20, AL 0.15). Details ▾Hide ▴
Evidence considered
- REVEL: 0.786 (pathogenic range). BayesDel: 0.144 (benign range). SpliceAI max delta: 0.20 (DL=0.20 borderline
- AL=0.15). Conflicting predictions.
Sources
PP5 No reputable source classifies this variant as pathogenic. ClinVar reports a single submission from Labcorp Genetics (formerly Invitae) classifying it as Uncertain significance (SCV002134937). PMID:28492532 is the Sherloc methodology paper and does not report this specific variant. PMID:20301782 is a GeneReviews chapter on ALK-related neuroblastic tumor susceptibility; its abstract does not mention this variant, and no full text is available to confirm variant-specific reporting. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- single submitter. No source classifies as pathogenic.
Sources
BA1 The variant is absent from gnomAD v2.1 and present at AF = 1.86 × 10⁻⁶ in gnomAD v4.1, far below the BA1 threshold of >1% (and the more conservative >5%). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.86e-06
- well below 1% BA1 threshold.
Sources
BS1 The variant frequency in gnomAD v4.1 (AF = 1.86 × 10⁻⁶, 0.00019%) is far below the non-VCEP BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 1.86e-06
- well below 0.3% BS1 threshold.
Sources
BS2 Observation of the variant at very low frequency in population databases (3 heterozygous alleles in gnomAD v4.1) does not meet BS2, which requires confirmed observation in a healthy adult individual for a disorder expected to be fully penetrant at an early age. The gnomAD population data lack phenotype confirmation and no homozygous observations were recorded. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 3 heterozygous alleles
- 0 homozygotes
- phenotype data unavailable.
Still missing
- No confirmed healthy adult carriers with phenotype data.
Sources
BP1 ALK-related neuroblastic tumor susceptibility is not a disorder where only truncating variants cause disease. Germline ALK pathogenic variants include both activating missense mutations in the tyrosine kinase domain and potential loss-of-function variants. Therefore, a missense variant does not meet BP1. Details ▾Hide ▴
Evidence considered
- ALK germline disease mechanism includes both missense and truncating variants
- not exclusively a truncating-variant disease.
Sources
pvs1_gene_context
BP4 Multiple lines of computational evidence do not concordantly suggest no impact on the gene product. REVEL score 0.786 supports a deleterious effect, contradicting BP4. BayesDel 0.144 is in the benign range, and SpliceAI delta 0.20 is borderline. The computational evidence is conflicting rather than consistently benign. Details ▾Hide ▴
Evidence considered
- REVEL 0.786 (pathogenic) conflicts with BP4
- BayesDel 0.144 (benign)
- SpliceAI max delta 0.20 (borderline). Not multiple concordant benign lines.
Sources
BP6 No reputable source classifies this variant as benign. ClinVar reports Uncertain significance from a single clinical laboratory (Labcorp/Invitae, SCV002134937). Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- criteria provided
- single submitter. No benign classification from any source.
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified for an established pathogenic variant with the same amino acid change (p.Gly1345Arg) resulting from a different nucleotide substitution. No literature or database reports a pathogenic G1345 variant at a different nucleotide position. Details ▾Hide ▴
Still missing
- No same-amino-acid pathogenic comparator identified in ClinVar or literature.
PS2 No de novo observation with confirmed maternity and paternity was identified for this variant in any source. Details ▾Hide ▴
Still missing
- No de novo data available.
PS4 No case-control studies or cohort data comparing variant prevalence in affected versus unaffected individuals were identified. ClinVar contains a single clinical laboratory submission (Labcorp/Invitae) classifying the variant as Uncertain significance, but this does not provide case counts for PS4. Details ▾Hide ▴
Evidence considered
- ClinVar SCV002134937: single submitter
- Uncertain significance
- no case counts.
Still missing
- No case-control or cohort data
- no observational series with affected counts.
Sources
PM6 No assumed de novo observations (without confirmed maternity/paternity) were identified for this variant in any source. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No cosegregation data in multiple affected family members were identified for this variant. Details ▾Hide ▴
Still missing
- No segregation studies available.
PP2 HCI prior probability is not available for ALK (gene not supported). No CSPEC/VCEP PP2 rule is available. Without gene-level missense constraint metrics (e.g., Z-score, oe ratio), PP2 cannot be reliably assessed. Details ▾Hide ▴
Evidence considered
- HCI prior: gene_not_supported. No VCEP PP2 rule for ALK.
Still missing
- No gene-level missense constraint data available for ALK.
PP4 No patient phenotype or family history data are available to assess whether the phenotype is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No clinical phenotype data available.
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant. Details ▾Hide ▴
Still missing
- No variant-specific benign functional data available.
BS4 No segregation data in affected family members are available to assess lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No segregation studies available.
BP2 No data are available regarding observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No trans-phase data available.
BP5 No data are available regarding observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternate-molecular-basis data available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_004304.4:c.4033G>A is a missense variant (p.Gly1345Arg); it does not fall into the null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution in exon 27
- PVS1 variant assessment bucket = 'other'
- apply_generic_pvs1_framework = false.
Sources
PM5 N/ANo same-residue comparator missense variants with prior pathogenic classification were identified. PM5 candidate search returned no eligible comparators; automatic candidate harvesting was skipped due to inability to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- PM5 candidate collection returned 0 same-residue candidates with pathogenic classification.
Sources
pm5_candidates
BP3 N/AIn-frame deletions/insertions in a repetitive region without a known function — not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.4033G>A, p.Gly1345Arg), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
PS5 N/APS5 is not a criterion defined in the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). No VCEP/CSPEC framework with PS5 is available for ALK. Details ▾Hide ▴
Evidence considered
- PS5 not present in generic ACMG/AMP 2015 criteria.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- ALK
- Transcript
- NM_004304.4
- Coding (HGVS c.)
- NM_004304.4:c.4033G>A
- Protein (HGVS p.)
- NP_004295.2:p.(Gly1345Arg)
- GRCh38
- chr2:29197582 C>T
- GRCh37
- chr2:29420448 C>T
- ClinVar
- 1363092
Gene diagram
Every interpreted variant in ALK, mapped onto the exon structure of NM_004304.4. Select a row to find it on the plot.
ALKNM_004304.4
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 ALK
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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
3 / 1,613,830 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,830 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,180,024 | 2.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85893e-06; MAF= 0.00019%, 3/1613830 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54232e-06; MAF= 0.00025%, 3/1180024 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.786
- BayesDel
- 0.144
How the predictions were used
PP3 In silico predictions are conflicting and do not provide multiple concordant lines of computational evidence for a deleterious effect. REVEL score 0.786 supports pathogenicity, but BayesDel score 0.144 falls in the benign range, and SpliceAI max delta 0.20 is at the threshold of significance (DL 0.20, AL 0.15). Details ▾Hide ▴
Evidence considered
- REVEL: 0.786 (pathogenic range). BayesDel: 0.144 (benign range). SpliceAI max delta: 0.20 (DL=0.20 borderline
- AL=0.15). Conflicting predictions.
Sources
BP4 Multiple lines of computational evidence do not concordantly suggest no impact on the gene product. REVEL score 0.786 supports a deleterious effect, contradicting BP4. BayesDel 0.144 is in the benign range, and SpliceAI delta 0.20 is borderline. The computational evidence is conflicting rather than consistently benign. Details ▾Hide ▴
Evidence considered
- REVEL 0.786 (pathogenic) conflicts with BP4
- BayesDel 0.144 (benign)
- SpliceAI max delta 0.20 (borderline). Not multiple concordant benign lines.
Sources
BP7 N/AThis is a missense variant (c.4033G>A, p.Gly1345Arg), not a synonymous variant. BP7 applies only to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.786. BayesDel score = 0.144187.
2 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 20301782 ↗ALK-Related Neuroblastic Tumor Susceptibility.Adam MP et al. · 1993GeneReviews chapter on ALK-related neuroblastic tumor susceptibility (Marcus et al., updated 2020). NM_004304.4:c.4033G>A (p.Gly1345Arg) was not identified in the abstract.Does not name this variant
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc refinement of the ACMG-AMP variant classification guidelines (Nykamp et al., 2017). NM_004304.4:c.4033G>A (p.Gly1345Arg) was not reported in this methodology paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,613,830 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.200
Open source ↗
ClinVar
1 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/1363092/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-29420448-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-29197582-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004304.4%3Ac.4033…
- OncoKB ↗www.oncokb.org/gene/ALK/G1345R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ALK+c.4033G%3EA
- 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= 1.85893e-06; MAF= 0.00019%, 3/1613830 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54232e-06; MAF= 0.00025%, 3/1180024 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1363092)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.20). REVEL score = 0.786. BayesDel score = 0.144187.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma
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.