3-69959370-C-T

Variant names:

• chr3-69959370-C-T
• rs876657699
• NM_001354604.2:c.1129C>T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001354604.2(MITF):​c.1129C>T​(p.Arg377*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.45

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-69959370-C-T is Pathogenic according to our data. Variant chr3-69959370-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.1129C>T	p.Arg377*	stop_gained	Exon 9 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.808C>T	p.Arg270*	stop_gained	Exon 8 of 9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.1129C>T	p.Arg377*	stop_gained	Exon 9 of 10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.808C>T	p.Arg270*	stop_gained	Exon 8 of 9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Aug 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg270*) in the MITF gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MITF are known to be pathogenic (PMID: 8659547, 20127975). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Waardenburg syndrome (PMID: 27759048, 34142234). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228363). For these reasons, this variant has been classified as Pathogenic. -

Waardenburg syndrome type 2 Pathogenic:1

Dec 06, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in MITF is a nonsense variant predicted to create a premature stop codon, p.(Arg377*), in biologically relevant exon 9/10 expected to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 7874167, 7874168, 9499424, 27759048). This variant is absent from the population database gnomAD v4.1. This variant has been reported in multiple probands with deafness/syndromic deafness, and segregates with disease in a large four-generation family (PMID: 27759048, 38965328, 39107234; ClinVar: SCV001478214.1, SCV000271397.2). One of the individuals is a de novo occurrence the variant with unconfirmed parental relationships (ClinVar: SCV000271397.2). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PM6, PP1_Strong, PS4_Supporting, PVS1 -

not provided Pathogenic:1

Oct 31, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 150 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34142234, 27759048) -

Waardenburg syndrome type 2A Pathogenic:1

Jan 01, 2019

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Jan 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg371X variant in MITF has been identified by our laboratory in one indiv idual with hearing loss, which is assumed to have occurred de novo. It has not been reported in large population studies. This nonsense variant leads to a pr emature termination codon at position 371 and is located 51 nucleotides from the end of the penultimate (second to last) exon. Therefore, this variant is expect ed to undergo nonsense mediated mRNA decay (NMD) (Holbrook 2004) resulting in a n absent protein. However, due to its close location to the penultimate intron it could escape NMD and leading to a truncated protein. Heterozygous loss of fu nction variants in the MITF gene are well described in individuals with Waardenb urg syndrome. In summary, the p.Arg371X variant meets the criteria to be classi fied as pathogenic for hearing loss in an autosomal dominant manner. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.98
GERP RS		3.0

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: rs876657699; hg19: chr3-70008521; COSMIC: COSV58833666;