rs111033347

Variant names:

• chr11-77190708-CA-C
• rs111033347
• NM_000260.4:c.3764delA

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.3764delA​(p.Lys1255ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,593,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: MYO7A NM_000260.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.94

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 11-77190708-CA-C is Pathogenic according to our data. Variant chr11-77190708-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77190708-CA-C is described in Lovd as [Pathogenic]. Variant chr11-77190708-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.3764delA	p.Lys1255ArgfsTer8	frameshift_variant	Exon 30 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.3764delA	p.Lys1255ArgfsTer8	frameshift_variant	Exon 30 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.3764delA	p.Lys1255ArgfsTer8	frameshift_variant	Exon 30 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.3731delA	p.Lys1244ArgfsTer8	frameshift_variant	Exon 31 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.1307delA	p.Lys436ArgfsTer8	frameshift_variant	Exon 10 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.1604delA		non_coding_transcript_exon_variant	Exon 13 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000180 AC: 26 AN: 1441498 Hom.: 0 Cov.: 31 AF XY: 0.0000168 AC XY: 12 AN XY: 714780

Gnomad4 AFR exome AF: 0.0000303

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000227

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1 Pathogenic:2

-

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 02, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Nov 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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 (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27460420, 30337596, 17361009, 26969326, 21436283, 28041643, 31589614, 32581362, 33576163, 31479088) -

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys1255Argfs*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 clinical features of autosomal recessive MYO7A-related conditions (PMID: 17361009, 26969326, 27460420, 30337596, 31479088). This variant is also known as c.3763del. ClinVar contains an entry for this variant (Variation ID: 43223). For these reasons, this variant has been classified as Pathogenic. -

Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

Nov 02, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Usher syndrome type 1B Pathogenic:1

Dec 07, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Usher syndrome type 1;C1832475:Autosomal dominant nonsyndromic hearing loss 11;C1838701:Autosomal recessive nonsyndromic hearing loss 2 Pathogenic:1

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1

Jul 26, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys1255fs variant in MYO7A has been reported in two probands with Usher synd rome who were each compound heterozygous with a second pathogenic MYO7A variant (Roux 2011, Jaijo 2007). In addition, the Lys1255fs variant is predicted to caus e a frameshift, which alters the protein's amino acid sequence beginning at codo n 1255 and leads to a premature stop codon 8 codons downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this var iant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs111033347; hg19: chr11-76901753;