rs1555095933

Positions:

• chr11-77194384-C-CA

Variant summary

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

The NM_000260.4(MYO7A):​c.4184dupA​(p.Tyr1396fs) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.91

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 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 11-77194384-C-CA is Pathogenic according to our data. Variant chr11-77194384-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4184dupA	p.Tyr1396fs	frameshift_variant	32/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4184dupA	p.Tyr1396fs	frameshift_variant	32/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4184dupA	p.Tyr1396fs	frameshift_variant	32/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4151dupA	p.Tyr1385fs	frameshift_variant	33/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1727dupA	p.Tyr577fs	frameshift_variant	12/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2024dupA		non_coding_transcript_exon_variant	15/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	May 22, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with MYO7A related disorder (ClinVar ID: VCV000557498). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The frameshift c.4184dup (p.Tyr1396ValfsTer8) variant) in the MYO7A gene has been reported to be associated with MYO7A related disorder (Wang, Rongrong et al.,2017). The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant causes a frameshift starting with codon Tyrosine 1396, changes this amino acid to Valine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Tyr1396ValfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Mar 27, 2018

- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Dec 31, 2022

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 20, 2023

This sequence change creates a premature translational stop signal (p.Tyr1396Valfs*8) in the MYO7A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYO7A are known to be pathogenic (PMID: 8900236, 25404053). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 28281779). ClinVar contains an entry for this variant (Variation ID: 557498). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1555095933; hg19: chr11-76905429;