About MITF
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MITF c.218G>A, p.(Arg73His)
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
The variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.0018% (5/280628 alleles), gnomAD v4.1 AF = 0.0032% (51/1614094 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed. Absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple independent lines of computational evidence suggest no impact on gene product: REVEL score 0.285 (below 0.5, benign-leaning), BayesDel score -0.025 (neutral/benign-leaning, below damaging threshold), and SpliceAI max delta 0.0 (no predicted splicing impact). Three concordant in silico lines support a neutral effect.
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
51 / 1,614,094 alleles
gnomAD v4.1: 51 / 1,614,094 alleles. Recorded AF 3.15967e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.78172e-05; MAF= 0.00178%, 5/280628 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140017; MAF= 0.01400%, 1/7142 alleles, homozygotes = 0); grpmax FAF= 2.94e-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. MITF, a transcription factor involved in melanocyte differentiation, is altered by mutation and amplification in melanomas.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
3 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58891706, n = 3 times).
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: 2 met · 10 not met · 9 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_198159.3:c.218G>A (p.Arg73His) is a missense variant in MITF exon 2, classified under the generic ACMG/AMP 2015 framework as no CSPEC/VCEP framework is available for this gene.
The variant is present at extremely low frequency in gnomAD: v2.1 AF = 0.0018% (5/280628 alleles) and v4.1 AF = 0.0032% (51/1614094 alleles), with no homozygotes observed. This meets PM2 at supporting level.
Multiple lines of in silico evidence suggest a neutral effect: REVEL 0.285, BayesDel -0.025, and SpliceAI max delta 0.0, meeting BP4 at supporting benign level.
No variant-specific functional studies, case-control analyses, de novo reports, cosegregation data, or expert panel classifications were identified for this variant. The variant has been reported in ClinVar as Uncertain Significance by two clinical laboratories.
PVS1 is not applicable as the variant is missense. PM5 is not applicable as no pathogenic comparator exists at p.Arg73. BP1 is not applicable as MITF has known pathogenic missense variants. BP7 is not applicable as the variant is not synonymous. BP3, PM3, and PM4 were trivially not applicable per the assessment scope.
With one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 generic framework.
No criteria match.
Met · 2
PM2 SupportingThe variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.0018% (5/280628 alleles), gnomAD v4.1 AF = 0.0032% (51/1614094 alleles), both well below the 0.1% PM2 threshold. No homozygotes observed. Absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 5/280628 alleles (AF 1.78e-05)
- 0 homozygotes
- grpmax FAF 2.94e-06
- gnomAD v4.1: 51/1614094 alleles (AF 3.16e-05)
- grpmax FAF 2.665e-05
- Absent from gnomAD-Canada v1.0
- All sub-population AFs below 0.1%
Sources
BP4 SupportingMultiple independent lines of computational evidence suggest no impact on gene product: REVEL score 0.285 (below 0.5, benign-leaning), BayesDel score -0.025 (neutral/benign-leaning, below damaging threshold), and SpliceAI max delta 0.0 (no predicted splicing impact). Three concordant in silico lines support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.285 (<0.5
- benign-leaning)
- BayesDel: -0.025 (<0.13
- SpliceAI: max delta 0.00 (no splice alteration)
Sources
Not met · 10 · evaluated, threshold not reached
PS3 No well-established functional studies have demonstrated a damaging effect for p.Arg73His. OncoKB reports no variant-specific functional evidence. In silico scores (REVEL 0.285, BayesDel -0.025) do not constitute functional assay evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect with no variant-specific functional evidence
- No functional assay publications identified in exploratory PubMed search
Still missing
- No in vitro or in vivo functional data available for p.Arg73His
Sources
PS4 No formal case-control study comparing variant frequency in MITF-associated disease cases versus controls was identified. The variant prevalence in gnomAD (AF 0.003% in v4.1) is too low to support enrichment analysis without a dedicated study. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF 0.0018% (5/280628 alleles)
- gnomAD v4.1: AF 0.0032% (51/1614094 alleles)
- No case-control enrichment study identified
Still missing
- No case-control study of MITF variants in Waardenburg syndrome or melanoma cohorts
Sources
PM1 The variant lies in exon 2 within the N-terminal transactivation domain of MITF, but this region has not been established as a well-characterized mutational hot spot or critical functional domain by ClinGen or an authoritative VCEP. Many population-variable variants exist in this domain. Details ▾Hide ▴
Evidence considered
- No ClinGen-defined domain-specific constraint or mutational hot spot for MITF exon 2
- Exploratory search confirmed no curated domain-level PM1 support
Still missing
- No domain-specific constraint analysis curated for MITF variant interpretation
PP3 Multiple lines of in silico evidence do not support a deleterious effect: REVEL score 0.285 (below 0.5 threshold), BayesDel score -0.025 (below damaging threshold of 0.13), and SpliceAI max delta 0.0 (no predicted splicing impact). Computational evidence is consistent with a neutral/benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.285 (below damaging threshold of 0.5)
- BayesDel: -0.025 (below damaging threshold of 0.13)
- SpliceAI: max delta 0.00 (no splice impact predicted)
- HCI Prior: not available for this gene
Sources
BA1 BA1 requires an allele frequency >1% in any population. The highest observed sub-population frequency is 0.014% (gnomAD v2.1, Remaining individuals, AF 1.4e-04) and 0.008% (gnomAD v4.1, Remaining individuals, AF 8.0e-05), both far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 maximum sub-pop AF: 0.0207% (NFE_EST)
- overall AF: 0.0018%
- gnomAD v4.1 maximum sub-pop AF: 0.0091% (REMAINING_XX)
- overall AF: 0.0032%
- All sub-population frequencies well below 1%
Sources
BS1 BS1 requires an allele frequency >0.3% in any population for a dominant disorder. The highest observed sub-population frequency is 0.021% (gnomAD v2.1, NFE_EST, 1/4830 alleles) and 0.009% (gnomAD v4.1, REMAINING_XX, 3/32834 alleles), both well below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max sub-pop AF: 0.0207% (NFE_EST
- 1/4830)
- gnomAD v4.1 max sub-pop AF: 0.0091% (REMAINING_XX
- 3/32834)
- All sub-population frequencies below 0.3%
Sources
BS2 No observation of this variant in a healthy adult homozygous state or in trans with a known pathogenic MITF variant has been reported. The variant is absent as a homozygote in gnomAD (0 homozygotes across v2.1 and v4.1). Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD v2.1 and v4.1
- No observation in trans with a known pathogenic MITF variant identified
Still missing
- No compound heterozygote data available for MITF in gnomAD co-occurrence analysis
Sources
BS3 No well-established functional studies demonstrating no damaging effect for p.Arg73His have been identified. While in silico predictions (REVEL 0.285, BayesDel -0.025) suggest a benign effect, computational predictions alone do not constitute well-established functional evidence for BS3. Details ▾Hide ▴
Evidence considered
- No in vitro or in vivo functional assay publication identified for p.Arg73His
- In silico scores suggest benign effect but do not meet BS3 threshold for functional evidence
Still missing
- No experimental functional data (transactivation assay
- DNA binding
- etc.) for p.Arg73His
Sources
revelbayesdel
BS4 No formal segregation analysis demonstrating lack of segregation with disease in affected families is available. Population frequency data does not constitute direct evidence of non-segregation. Details ▾Hide ▴
Evidence considered
- No pedigree or family segregation study identified in literature search
- ClinVar submissions do not report segregation analysis
Still missing
- No family-based non-segregation evidence available
BP6 BP6 requires a reputable source to classify the variant as benign. ClinVar shows only Uncertain Significance classifications from two clinical laboratories; no expert panel or reputable source has classified this variant as benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 submissions
- both VUS
- No benign or likely benign classification from any submitter
- No expert panel review available
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo occurrence has been reported for this variant in the available evidence sources. Literature and database searches returned no de novo observations with confirmed maternity/paternity. Details ▾Hide ▴
Evidence considered
- Exploratory PubMed search for 'MITF c.218G>A de novo' returned no studies
- No de novo submission in ClinVar for this variant
Still missing
- No de novo data available
- population frequency makes de novo conviction unlikely for a rare dominant disorder
PM6 No assumed de novo occurrence without confirmation of maternity/paternity has been reported for this variant. Literature and database searches returned no de novo observations. Details ▾Hide ▴
Evidence considered
- Exploratory PubMed search for de novo MITF variants returned no relevant study
- No de novo submission in ClinVar
Still missing
- No de novo report exists
- variant frequency makes assumed de novo interpretation unlikely
PP1 No cosegregation data are available for this variant. No family studies reporting segregation of p.Arg73His with disease were identified in the literature. Details ▾Hide ▴
Evidence considered
- Exploratory search for MITF cosegregation studies returned no variant-specific data
Still missing
- No family segregation data available
PP2 PP2 requires a gene to have a low rate of benign missense variation with missense as a common disease mechanism. Without a CSPEC framework explicitly supporting PP2 for MITF, gene-level constraint data alone is insufficient to apply this criterion. Details ▾Hide ▴
Evidence considered
- MITF has known pathogenic missense variants (e.g.
- p.E318K in melanoma)
- No CSPEC/VCEP framework available to confirm PP2 applicability
Still missing
- No CSPEC-level gene constraint assessment available for MITF PP2
PP4 The variant is reported in ClinVar as Uncertain Significance by two clinical laboratories. Without detailed phenotype information, specific syndromic features, or expert panel review, the patient phenotype data is insufficient to apply PP4. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 submissions
- both VUS (St. Jude
- CeGaT)
- No expert panel review
- No detailed phenotype data available
Still missing
- No detailed clinical phenotype available for assessment of disease specificity
Sources
PP5 No reputable source (expert panel or clinical laboratory with strong diagnostic track record) has classified this variant as pathogenic. ClinVar shows two independent VUS classifications, neither from an expert panel. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (2 clinical laboratories)
- No expert panel (ENIGMA
- ClinGen
- etc.) classification available
Sources
BP2 No observation of this variant in trans with a known pathogenic MITF variant has been reported. Exploratory search of gnomAD co-occurrence data and literature found no documented case of compound heterozygosity with a pathogenic MITF variant. Details ▾Hide ▴
Evidence considered
- Literature and database search found no trans configuration with a pathogenic MITF variant
Still missing
- No gnomAD co-occurrence analysis available for MITF
BP5 No case-level data indicating an alternate molecular basis for disease was available. Clinical context was not provided for this assessment. Details ▾Hide ▴
Still missing
- No case-level data to determine if an alternative genetic cause was identified
PS5 No alternative causative variant was identified in the case data to establish an alternate molecular basis for disease. Case-level clinical context was not provided for assessment. Details ▾Hide ▴
Still missing
- No case-level data available to determine if an alternate molecular cause was established
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Arg73His); it does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is missense c.218G>A (p.Arg73His) in exon 2
- No canonical splice consensus involvement
- Variant bucket classified as 'other' by PVS1 scaffold
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant at the same amino acid position (p.Arg73) resulting from a different nucleotide change was identified in ClinVar, COSMIC, or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic or likely pathogenic same-amino-acid comparator at p.Arg73
- PM5 candidate search returned zero same-residue candidates
Sources
clinvar ↗pm5_candidates
PM5 N/ANo pathogenic or likely pathogenic comparator variant at the same amino acid residue (p.Arg73) with a different missense change was identified in ClinVar or other curated sources. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvest returned zero same-residue candidates
- ClinVar contains no P/LP classification at p.Arg73 with a different amino acid change
Sources
pm5_candidates
BP1 N/ABP1 is intended for missense variants in genes where only truncating variants are known to cause disease. MITF has well-established pathogenic missense variants (e.g., p.E318K in familial melanoma and Waardenburg syndrome type 2A), so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- MITF p.E318K is a well-characterized pathogenic missense variant associated with melanoma and Waardenburg syndrome
- Missense is a recognized disease mechanism for MITF
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.218G>A, p.Arg73His). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MITF
- Transcript
- NM_198159.3
- Coding (HGVS c.)
- NM_198159.3:c.218G>A
- Protein (HGVS p.)
- NP_937802.1:p.(Arg73His)
- GRCh38
- chr3:69879247 G>A
- GRCh37
- chr3:69928398 G>A
- ClinVar
- 3762533, 3377783
- COSMIC
- COSV58891706
Gene diagram
Every interpreted variant in MITF, mapped onto the exon structure of NM_198159.3. Select a row to find it on the plot.
MITFNM_198159.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MITF
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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
51 / 1,614,094 alleles
AF 3.16e-05 · 0 homozygotes · FAF 2.67e-05
gnomAD v2.1
5 / 280,628 alleles
AF 1.78e-05 · 0 homozygotes · FAF 2.94e-06
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 3.2e-05 · 51 / 1,614,094 alleles · 0 hom · FAF 2.7e-05
| Remaining individuals5 / 62,490 | 8e-05 |
| European (non-Finnish)42 / 1,180,054 | 3.6e-05 |
| South Asian3 / 91,094 | 3.3e-05 |
| Admixed American1 / 60,008 | 1.7e-05 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.8e-05 · 5 / 280,628 alleles · 0 hom · FAF 2.9e-06
| Remaining individuals1 / 7,142 | 0.00014 |
| South Asian1 / 30,602 | 3.3e-05 |
| European (non-Finnish)3 / 128,394 | 2.3e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish).
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.15967e-05; MAF= 0.00316%, 51/1614094 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00128e-05; MAF= 0.00800%, 5/62490 alleles, homozygotes = 0); grpmax FAF= 2.665e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.78172e-05; MAF= 0.00178%, 5/280628 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140017; MAF= 0.01400%, 1/7142 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.285
- BayesDel
- -0.025
How the predictions were used
BP4 SupportingMultiple independent lines of computational evidence suggest no impact on gene product: REVEL score 0.285 (below 0.5, benign-leaning), BayesDel score -0.025 (neutral/benign-leaning, below damaging threshold), and SpliceAI max delta 0.0 (no predicted splicing impact). Three concordant in silico lines support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.285 (<0.5
- benign-leaning)
- BayesDel: -0.025 (<0.13
- SpliceAI: max delta 0.00 (no splice alteration)
Sources
PP3 Multiple lines of in silico evidence do not support a deleterious effect: REVEL score 0.285 (below 0.5 threshold), BayesDel score -0.025 (below damaging threshold of 0.13), and SpliceAI max delta 0.0 (no predicted splicing impact). Computational evidence is consistent with a neutral/benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.285 (below damaging threshold of 0.5)
- BayesDel: -0.025 (below damaging threshold of 0.13)
- SpliceAI: max delta 0.00 (no splice impact predicted)
- HCI Prior: not available for this gene
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.218G>A, p.Arg73His). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.285. BayesDel score = -0.0249543.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
51 / 1,614,094 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/3377783/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-69928398-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-69879247-G-A?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_198159.3%3Ac.218G…
- OncoKB ↗www.oncokb.org/gene/MITF/R73H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=134730094
- 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= 3.15967e-05; MAF= 0.00316%, 51/1614094 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 8.00128e-05; MAF= 0.00800%, 5/62490 alleles, homozygotes = 0); grpmax FAF= 2.665e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.78172e-05; MAF= 0.00178%, 5/280628 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000140017; MAF= 0.01400%, 1/7142 alleles, homozygotes = 0); grpmax FAF= 2.94e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 3377783)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.285. BayesDel score = -0.0249543.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MITF, a transcription factor involved in melanocyte differentiation, is altered by mutation and amplification in melanomas.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58891706, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.