rs111033510

Positions:

• chr11-77174772-T-TAG

Variant summary

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

The NM_000260.4(MYO7A):​c.1952_1953insAG​(p.Cys652GlyfsTer11) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.45

Genes affected

MYO7A (HGNC:7606): (myosin VIIA) This gene is a member of the myosin gene family. Myosins are mechanochemical proteins characterized by the presence of a motor domain, an actin-binding domain, a neck domain that interacts with other proteins, and a tail domain that serves as an anchor. This gene encodes an unconventional myosin with a very short tail. Defects in this gene are associated with the mouse shaker-1 phenotype and the human Usher syndrome 1B which are characterized by deafness, reduced vestibular function, and (in human) retinal degeneration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

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 11-77174772-T-TAG is Pathogenic according to our data. Variant chr11-77174772-T-TAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43165.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.1952_1953insAG	p.Cys652GlyfsTer11	frameshift_variant	17/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.1952_1953insAG	p.Cys652GlyfsTer11	frameshift_variant	17/49	1	NM_000260.4	ENSP00000386331
MYO7A	ENST00000409619.6	c.1919_1920insAG	p.Cys641GlyfsTer11	frameshift_variant	18/50	1		ENSP00000386635
MYO7A	ENST00000458637.6	c.1952_1953insAG	p.Cys652GlyfsTer11	frameshift_variant	17/49	1		ENSP00000392185	P1
MYO7A	ENST00000409893.6	c.17_18insAG	p.Cys7GlyfsTer11	frameshift_variant	1/11	5		ENSP00000386689

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 13, 2009

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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: rs111033510; hg19: chr11-76885818;