NM_198159.3:c.394C>A (p.Gln132Lys) is a missense variant in MITF exon 3. It is present at very low frequency in population databases (gnomAD v2.1 AF=0.0198%; v4.1 AF=0.0126%) with no homozygotes, meeting PM2 at supporting level.1 Multiple in silico tools predict a benign effect: REVEL score 0.26 (benign), BayesDel score -0.0715 (benign), and SpliceAI max delta 0.05 (no predicted splicing impact), meeting BP4 at supporting level.2 The variant has been classified as Uncertain Significance by 7 clinical laboratories in ClinVar (Variation ID: 493364). No functional studies, segregation data, or case-control evidence have been reported.3 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and does not meet the threshold for Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant is classified as Uncertain Significance.4
MITF
Final classification
VUS
MITF c.394C>A · p.Gln132Lys
MITF
NM_198159.3:c.394C>A (p.Gln132Lys) is a missense variant in MITF exon 3. It is present at very low frequency in population databases (gnomAD v2.1 AF=0.0198%; v4.1 AF=0.0126%) with no homozygotes, meeting PM2 at supporting level.
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; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
MITF c.394C>A
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_198159.3 · variants mapped to exon structure
MITF
NM_198159.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_198159.3:c.394C>A is absent from gnomAD-Canada and present at very low frequency in gnomAD v2.1 (AF=0.000198, 56/282,620 alleles) and v4.1 (AF=0.000126, 203/1,613,992 alleles), both below the 0.1% PM2 threshold. No homozygotes observed.
gnomAD v2.1: AF=0.0198%56/282620 alleles
✓
BP4
supporting
Benign
Multiple in silico tools predict a benign effect for p.Gln132Lys. REVEL score is 0.26 (benign, well below 0.5 pathogenic threshold), BayesDel score is -0.0715 (benign), and SpliceAI predicts no splicing impact (max delta=0.05). All three independent computational predictors are concordant for a benign interpretation.
REVEL: 0.26 (benign)BayesDel: -0.0715 (benign)SpliceAI max delta: 0.05 (no predicted splicing alteration)
Assessed · not applied
Pathogenic
PVS1
NM_198159.3:c.394C>A is a missense variant (p.Gln132Lys).
PS1
No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution (Gln132Lys) with an established pathogenic classification.
PS2
No de novo observation reported for NM_198159.3:c.394C>A.
PS3
No functional studies evaluating the biological effect of p.Gln132Lys have been identified.
PS4
No case-control studies or statistically enriched observation in affected individuals versus controls have been reported for this variant.
PM1
Residue Gln132 does not lie within a statistically significant mutational hotspot in MITF.
PM6
No de novo observation reported for this variant with confirmed maternity and paternity.
PP1
No segregation data available for this variant in affected families.
PP2
Insufficient evidence that MITF has a low rate of benign missense variation and that missense variants are a common disease mechanism.
PP3
In silico tools do not support a deleterious effect.
PP4
No patient phenotype data are available to evaluate whether the proband's clinical presentation is specific for MITF-related disease.
PP5
No reputable source reports this variant as pathogenic.
Benign
BA1
Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), well below the 1% BA1 threshold.
BS1
Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), below the 0.3% BS1 threshold for a rare disease variant.
BS2
Although this variant is observed in gnomAD (56 heterozygous alleles in v2.1, 203 in v4.1), no homozygous observations exist, and no observation in trans with a known pathogenic MITF variant has been reported.
BS3
No well-established functional studies demonstrate that p.Gln132Lys has no deleterious effect on protein function.
BS4
No evidence of non-segregation with disease in affected families.
BP1
BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic MITF variant.
BP5
No alternative molecular basis for disease has been identified in the proband.
BP6
No reputable source reports this variant as benign.
N/A · 2
PM5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000125775; MAF= 0.01258%, 203/1613992 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000164407; MAF= 0.01644%, 194/1180002 alleles, homozygotes = 0); grpmax FAF= 0.0001452.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000198146; MAF= 0.01981%, 56/282620 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000403082; MAF= 0.04031%, 52/129006 alleles, homozygotes = 0); grpmax FAF= 0.0008586.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016290182450043442, 3/18416 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.013%
· 203 / 1,613,992
0 hom · FAF 0.015%
0 hom · FAF 0.015%
European (non-Finnish) 194 / 1,180,002 |
0.016% |
Remaining individuals 6 / 62,484 |
0.0096% |
Ashkenazi Jewish 1 / 29,606 |
0.0034% |
Admixed American 1 / 59,998 |
0.0017% |
European (Finnish) 1 / 64,048 |
0.0016% |
+ 5 not observed (Amish, East Asian, Middle Eastern, South Asian, African/African American)
gnomAD v2.1
0.02%
· 56 / 282,620
0 hom · FAF 0.086%
0 hom · FAF 0.086%
European (non-Finnish) 52 / 129,006 |
0.04% |
Remaining individuals 2 / 7,224 |
0.028% |
Ashkenazi Jewish 1 / 10,358 |
0.0097% |
European (Finnish) 1 / 25,118 |
0.004% |
+ 4 not observed (African/African American, Admixed American, East Asian, South Asian)
gnomAD Canada 🇨🇦
0.016%
· 3 / 18,416
0 hom · FAF 0.0069%
0 hom · FAF 0.0069%
European (non-Finnish) 3 / 11,738 |
0.026% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 493364)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05). REVEL score = 0.26. BayesDel score = -0.0715447.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
24033266 ↗
A systematic approach to assessing the clinical significance of genetic variants.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR