rs1553705282

chr3-69959385-GA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001354604.2(MITF):c.1145del(p.Glu382GlyfsTer37) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. E382E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 Likely_pathogenic. Variant got 7 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 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-69959385-GA-G is Pathogenic according to our data. Variant chr3-69959385-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 14274.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-69959385-GA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_001354604.2	c.1145del	p.Glu382GlyfsTer37	frameshift_variant	9/10	ENST00000352241.9
MITF	NM_000248.4	c.824del	p.Glu275GlyfsTer37	frameshift_variant	8/9	ENST00000394351.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.1145del	p.Glu382GlyfsTer37	frameshift_variant	9/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.824del	p.Glu275GlyfsTer37	frameshift_variant	8/9	1	NM_000248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Waardenburg syndrome type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1997

- -

Computational scores

Source: dbNSFP v4.3

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: rs1553705282; hg19: chr3-70008536;