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.1 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.2 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.3 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.4 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.5
MITF
Final classification
VUS
MITF c.218G>A · p.Arg73His
MITF
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.
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.
Classification rationale
PM2
BP4
VUS
MITF c.218G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_198159.3 · variants mapped to exon structure
MITF
NM_198159.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 5/280628 alleles (AF 1.78e-05)0 homozygotesgrpmax FAF 2.94e-06
✓
BP4
supporting
Benign
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: 0.285 (<0.5benign-leaning)BayesDel: -0.025 (<0.13
Assessed · not applied
Pathogenic
PS2
No de novo occurrence has been reported for this variant in the available evidence sources.
PS3
No well-established functional studies have demonstrated a damaging effect for p.Arg73His.
PS4
No formal case-control study comparing variant frequency in MITF-associated disease cases versus controls was identified.
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.
PM6
No assumed de novo occurrence without confirmation of maternity/paternity has been reported for this variant.
PP1
No cosegregation data are available for this variant.
PP2
PP2 requires a gene to have a low rate of benign missense variation with missense as a common disease mechanism.
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).
PP4
The variant is reported in ClinVar as Uncertain Significance by two clinical laboratories.
PP5
No reputable source (expert panel or clinical laboratory with strong diagnostic track record) has classified this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in any population.
BS1
BS1 requires an allele frequency >0.3% in any population for a dominant disorder.
BS2
No observation of this variant in a healthy adult homozygous state or in trans with a known pathogenic MITF variant has been reported.
BS3
No well-established functional studies demonstrating no damaging effect for p.Arg73His have been identified.
BS4
No formal segregation analysis demonstrating lack of segregation with disease in affected families is available.
BP2
No observation of this variant in trans with a known pathogenic MITF variant has been reported.
BP5
No case-level data indicating an alternate molecular basis for disease was available.
BP6
BP6 requires a reputable source to classify the variant as benign.
N/A · 6
PVS1 · PS1 · PM5 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
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.
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.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0032%
· 51 / 1,614,094
0 hom · FAF 0.0027%
0 hom · FAF 0.0027%
Remaining individuals 5 / 62,490 |
0.008% |
European (non-Finnish) 42 / 1,180,054 |
0.0036% |
South Asian 3 / 91,094 |
0.0033% |
Admixed American 1 / 60,008 |
0.0017% |
+ 6 not observed (European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0018%
· 5 / 280,628
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
Remaining individuals 1 / 7,142 |
0.014% |
South Asian 1 / 30,602 |
0.0033% |
European (non-Finnish) 3 / 128,394 |
0.0023% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
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 previously been reported in somatic cancers (COSMIC; COSV58891706, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links