NM_198159.3:c.394C>A

MITF · NP_937802.1:p.(Gln132Lys) · NM_198159.3

GRCh37: chr3:69987012 C>A · GRCh38: chr3:69937861 C>A

Gene: MITF Transcript: NM_198159.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MITF

Transcript

NM_198159.3

Protein

NP_937802.1:p.(Gln132Lys)

gnomAD AF

0.00012577509677867053 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	NM_198159.3:c.394C>A is a missense variant (p.Gln132Lys). It does not fall into any default generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense variants under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution (Gln132Lys) with an established pathogenic classification. No PS1 comparator identified.
PS2	Not met	No de novo observation reported for NM_198159.3:c.394C>A. No confirmed maternity/paternity data available.
PS3	Not met	No functional studies evaluating the biological effect of p.Gln132Lys have been identified. OncoKB classifies this variant as having Unknown Oncogenic Effect. ClinVar submissions explicitly note that functional studies have not confirmed any predicted effect.	oncokb clinvar
PS4	Not met	No case-control studies or statistically enriched observation in affected individuals versus controls have been reported for this variant.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). No reputable source reports this variant as pathogenic.
PM1	Not met	Residue Gln132 does not lie within a statistically significant mutational hotspot in MITF. Hotspot analysis shows no significant enrichment at this position.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue (Gln132) pathogenic comparator variant with a different amino acid change was identified. Automated PM5 candidate harvesting returned no candidates.	pm5_candidates
PM6	Not met	No de novo observation reported for this variant with confirmed maternity and paternity.
PP1	Not met	No segregation data available for this variant in affected families.
PP2	Not met	Insufficient evidence that MITF has a low rate of benign missense variation and that missense variants are a common disease mechanism. MITF has both gain-of-function (p.Glu318Lys in melanoma) and loss-of-function mechanisms; missense constraint metrics are not available to support PP2.
PP3	Not met	In silico tools do not support a deleterious effect. REVEL score is 0.26 (below the 0.5 threshold for pathogenicity), BayesDel score is -0.0715 (benign range), and SpliceAI predicts no splicing impact (max delta=0.05). All computational predictors favor a benign interpretation.	revel bayesdel spliceai
PP4	Not met	No patient phenotype data are available to evaluate whether the proband's clinical presentation is specific for MITF-related disease.
PP5	Not met	No reputable source reports this variant as pathogenic. ClinVar classification is Uncertain Significance (7 clinical laboratories, single submitter review status). No expert panel has classified this variant as pathogenic.	clinvar
BA1	Not met	Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), well below the 1% BA1 threshold. The variant is not common enough to be considered a standing benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	Maximum population allele frequency is 0.0403% in NFE (gnomAD v2.1), below the 0.3% BS1 threshold for a rare disease variant.	gnomad_v2 gnomad_v4
BS2	Not met	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. Without homozygous or in-trans data, BS2 cannot be applied under generic ACMG/AMP.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate that p.Gln132Lys has no deleterious effect on protein function.
BS4	Not met	No evidence of non-segregation with disease in affected families.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. MITF has both missense (p.Glu318Lys in melanoma, Waardenburg syndrome type 2A missense variants) and truncating disease mechanisms. BP1 is not applicable.
BP2	Not met	No observation of this variant in trans with a known pathogenic MITF variant.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in the proband. BP5 requires a different pathogenic variant in the same gene or a different gene explaining the phenotype.
BP6	Not met	No reputable source reports this variant as benign. ClinVar classification is Uncertain Significance across 7 clinical laboratories.	clinvar
BP7	N/A	NM_198159.3:c.394C>A is a missense variant (p.Gln132Lys), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.