rs1195515853

chr3-69959281-G-Achr3-69959281-G-Cchr3-69959281-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001354604.2(MITF):c.1040G>A(p.Arg347His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: MITF NM_001354604.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 10.0

Genes affected

MITF (HGNC:7105): (melanocyte inducing transcription factor) The protein encoded by this gene is a transcription factor that contains both basic helix-loop-helix and leucine zipper structural features. The encoded protein regulates melanocyte development and is responsible for pigment cell-specific transcription of the melanogenesis enzyme genes. Heterozygous mutations in the this gene cause auditory-pigmentary syndromes, such as Waardenburg syndrome type 2 and Tietz syndrome. [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_001354604.2	c.1040G>A	p.Arg347His	missense_variant	9/10	ENST00000352241.9
MITF	NM_000248.4	c.719G>A	p.Arg240His	missense_variant	8/9	ENST00000394351.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.1040G>A	p.Arg347His	missense_variant	9/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.719G>A	p.Arg240His	missense_variant	8/9	1	NM_000248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250532 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461766 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727182

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 10, 2019

The p.Arg240His variant in MITF has been reported by our laboratory in 1 individual with hearing loss, and was also identified in a reportedly unaffected parent. This variant was identified in 0.0008% (1/113036) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg240His variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3. -

Tietz syndrome;C1860339:Waardenburg syndrome type 2A;C3152204:Melanoma, cutaneous malignant, susceptibility to, 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 240 of the MITF protein (p.Arg240His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with non-syndromic hearing loss (PMID: 32728090). ClinVar contains an entry for this variant (Variation ID: 505101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MITF protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects MITF function (PMID: 32728090). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

MITF-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 06, 2023

The MITF c.719G>A variant is predicted to result in the amino acid substitution p.Arg240His. This variant was reported in the homozygous state in three siblings from a consanguineous family with nonsyndromic hearing loss without pigmentation abnormalities (described as p.Arg341His, Thongpradit et al. 2020. PubMed ID: 32728090). Five heterozygous carriers in this family were reported to be asymptomatic. Functional studies showed that this variant results in reduced transcriptional activity and altered subcellular localization (Thongpradit et al. 2020. PubMed ID: 32728090). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Different nucleotide substitutions affecting the same amino acid (p.Arg240Gly and p.Arg240Cys) have been reported in the heterozygous state in four individuals with nonsyndromic hearing loss from three families but was also present in two unaffected family members, and in the homozygous state in one individual with Waardenburg syndrome (Thongpradit et al. 2020. PubMed ID: 32728090; Somashekar et al. 2019. PubMed ID: 30394532; described as c.1021C>G, Li et al. 2021. PubMed ID: 33724713; Zhang et al. 2018. PubMed ID: 29484430). Although we suspect that the c.719G>A (p.Arg240His) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 07, 2023

Observed in homozygous state in three siblings with nonsyndromic hearing loss in the literature; heterozygous parents were unaffected; reported as c.1022G>A p.(R341H) using alternate nomenclature (Thongpradit et al., 2020); Published functional studies suggest a reduction of TYR promoter activity compared to wildtype and mislocalization of the resulting protein, however, the effect on downstream target genes was not assessed (Thongpradit et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32728090) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.7	D;D;.;D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;.;D;D;D;D;D;D;D
Sift4G	Uncertain	0.018	D;D;.;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;D;D;.;D;D;.
Vest4		0.95
MutPred		0.65		Loss of MoRF binding (P = 0.0093);.;Loss of MoRF binding (P = 0.0093);.;.;.;.;.;.;.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.80
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1195515853; hg19: chr3-70008432; COSMIC: COSV58833314;