rs1553703619

chr3-69949059-C-CTCGGGAAACTTGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001354604.2(MITF):c.773_785dup(p.Asp263GlyfsTer5) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MITF NM_001354604.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.75

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 12 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 3-69949059-C-CTCGGGAAACTTGA is Pathogenic according to our data. Variant chr3-69949059-C-CTCGGGAAACTTGA is described in ClinVar as [Pathogenic]. Clinvar id is 505620.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MITF	NM_000248.4	c.452_464dup	p.Asp156GlyfsTer5	frameshift_variant	5/9	ENST00000394351.9
MITF	NM_001354604.2	c.773_785dup	p.Asp263GlyfsTer5	frameshift_variant	6/10	ENST00000352241.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MITF	ENST00000352241.9	c.773_785dup	p.Asp263GlyfsTer5	frameshift_variant	6/10	1	NM_001354604.2	P4
MITF	ENST00000394351.9	c.452_464dup	p.Asp156GlyfsTer5	frameshift_variant	5/9	1	NM_000248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 10, 2017

The p.Asp263fs variant in MITF has not previously been reported in individuals w ith hearing loss or Waardenburg syndrome or in large population studies. This va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 263 and leads to a premature termination codon 5 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss-of-function of the MITF gene is an establi shed disease mechanism for Waardenburg syndrome. In summary, this variant meets criteria to be classified as pathogenic for Waardenburg syndrome in an autosomal dominant manner based on the predicted impact on the protein and extremely low allele frequency in the general population. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553703619; hg19: chr3-69998210;