chr3-69939164-C-T

Position:

• chr3-69939164-C-T

Variant summary

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

The ENST00000352241.9(MITF):​c.649C>T​(p.Arg217Ter) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R217R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF ENST00000352241.9 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.33

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 3-69939164-C-T is Pathogenic according to our data. Variant chr3-69939164-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 488040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-69939164-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MITF	NM_001354604.2	c.649C>T	p.Arg217Ter	stop_gained	4/10	ENST00000352241.9	NP_001341533.1
MITF	NM_000248.4	c.328C>T	p.Arg110Ter	stop_gained	3/9	ENST00000394351.9	NP_000239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MITF	ENST00000352241.9	c.649C>T	p.Arg217Ter	stop_gained	4/10	1	NM_001354604.2	ENSP00000295600	P4
MITF	ENST00000394351.9	c.328C>T	p.Arg110Ter	stop_gained	3/9	1	NM_000248.4	ENSP00000377880

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 2A Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Laboratory of Human Genetics, Universidade de São Paulo	Mar 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change creates a premature translational stop signal (p.Arg110*) 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 autosomal dominant Waardenburg syndrome (PMID: 20478267, 23512835). ClinVar contains an entry for this variant (Variation ID: 488040). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2022

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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29407415, 27759048, 20478267, 27562378, 29798271, 33045145, 26417640, 30936914, 34323021, 27535533, 23512835) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
Vest4		0.95
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1553702006; hg19: chr3-69988315; COSMIC: COSV58829776; COSMIC: COSV58829776;