Variant classification summary

NM_198159.3:c.218G>A

MITF · NP_937802.1:p.(Arg73His) · NM_198159.3

GRCh37: chr3:69928398 G>A · GRCh38: chr3:69879247 G>A

Gene: MITF Transcript: NM_198159.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

MITF

Transcript

NM_198159.3

Protein

NP_937802.1:p.(Arg73His)

gnomAD AF

3.1596672808399014e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

6

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.

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	N/A	This 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).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No 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.	clinvar pm5_candidates
PS2	Not assessed	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.
PS3	Not met	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.	oncokb revel bayesdel
PS4	Not met	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.	gnomad_v2 gnomad_v4
PS5	Not assessed	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.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	No 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not assessed	No cosegregation data are available for this variant. No family studies reporting segregation of p.Arg73His with disease were identified in the literature.
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.	clinvar
PP5	Not assessed	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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).	gnomad_v2 gnomad_v4
BS3	Not met	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.	revel bayesdel
BS4	Not met	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.
BP1	N/A	BP1 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.
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a missense substitution.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not assessed	No case-level data indicating an alternate molecular basis for disease was available. Clinical context was not provided for this assessment.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (c.218G>A, p.Arg73His).

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