3-69959325-C-T

Variant names:

• chr3-69959325-C-T
• rs1057517966
• NM_001354604.2:c.1084C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001354604.2(MITF):​c.1084C>T​(p.Arg362*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MITF NM_001354604.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 1.93

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-69959325-C-T is Pathogenic according to our data. Variant chr3-69959325-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372755.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69959325-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MITF	NM_001354604.2	c.1084C>T	p.Arg362*	stop_gained	Exon 9 of 10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.763C>T	p.Arg255*	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.1084C>T	p.Arg362*	stop_gained	Exon 9 of 10	1	NM_001354604.2	ENSP00000295600.8
MITF	ENST00000394351.9	c.763C>T	p.Arg255*	stop_gained	Exon 8 of 9	1	NM_000248.4	ENSP00000377880.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 31, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate a damaging effect on trans-activation of the TYR promoter, leading to haploinsufficiency (Wang et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20478267, 24194866, 22320238, 26512583, 28777840, 29407415, 29094203, 29531335, 33045145, 27759048, 30394532, 30936914, 33597575) -

Dec 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Waardenburg syndrome type 2A Pathogenic:2

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2017

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

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

Oct 25, 2023

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.Arg255*) 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 individual(s) with Waardenburg syndrome (PMID: 20478267, 22320238, 24194866, 29531335, 30394532). ClinVar contains an entry for this variant (Variation ID: 372755). For these reasons, this variant has been classified as Pathogenic. -

MITF-related disorder Pathogenic:1

Sep 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MITF c.763C>T variant is predicted to result in premature protein termination (p.Arg255*). This variant was reported in multiple individuals with Waardenburg syndrome (Chen et al. 2010. PubMed ID: 20478267; Yang et al. 2013. PubMed ID: 24194866; Kim et al. 2015. PubMed ID: 26512583). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in MITF are expected to be pathogenic. This variant is interpreted as pathogenic. -

Congenital sensorineural hearing impairment Pathogenic:1

May 15, 2018

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
Vest4		0.99
GERP RS		5.2

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: rs1057517966; hg19: chr3-70008476;