Variant rs782539587 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000260.4(MYO7A):c.1258A>T(p.Lys420Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000958 in 1,461,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

MYO7A
NM_000260.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 5.04

Variant links:

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]

MYO7A links:

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ACMG classification

Classification made for transcript

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 11-77161030-A-T is Pathogenic according to our data. Variant chr11-77161030-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 504508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77161030-A-T is described in Lovd as [Pathogenic]. Variant chr11-77161030-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.1258A>T	p.Lys420Ter	stop_gained	12/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.1258A>T	p.Lys420Ter	stop_gained	12/49	1	NM_000260.4	ENSP00000386331		Q13402-1
MYO7A	ENST00000458637.6 linkuse as main transcript	c.1258A>T	p.Lys420Ter	stop_gained	12/49	1		ENSP00000392185	P1	Q13402-2
MYO7A	ENST00000409619.6 linkuse as main transcript	c.1225A>T	p.Lys409Ter	stop_gained	13/50	1		ENSP00000386635		Q13402-8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

248542

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000657

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461390

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726918

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 05, 2024	Nonsense 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; This variant is associated with the following publications: (PMID: 25525159, 16963483, 29692870, 31479088, 31456290, 31541171, 31964843) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 21, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 504508). This premature translational stop signal has been observed in individuals with MYO7A-related conditions (PMID: 23770805, 29692870, 31479088). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs782539587, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Lys420*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2019	- -

Autosomal recessive nonsyndromic hearing loss 2

Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital

Feb 26, 2019

- -

Usher syndrome type 1

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Feb 09, 2023

The MYO7A c.1258A>T variant is classified as a PATHOGENIC variant (PVS1, PM3_Strong) This variant is a single nucleotide change in exon 12/49 of the MYO7A gene, which is predicted to result in premature termination of the protein product at codon 420, causing loss of normal protein function (PVS1). The variant has been reported homozygous or compound heterozygous with another pathogenic MYO7A variant in multiple unrelated individuals affected with hearing loss or Usher syndrome (PMID: 22135276, 23770805, 27460420, 29692870, 31479088) (PM3_Strong). The variant has been reported in dbSNP (rs782539587) but is rare in population databases (gmomAD v2: 4/124267, 0 homozygotes). The variant has been reported in ClinVar (Variation ID: #504508) and HGMD (Accession no.: CM071018) as pathogenic/disease causing. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 11, 2017

The p.Lys420X variant in MYO7A has been identified in the homozygous or compound heterozygous state in 6 individuals with clinical features of Usher syndrome (B onnet 2016, Le Quesne Stabej 2012, Shahzad 2013). In one study, this variant was identified in the homozygous state in 4 separate families of Pakistani descent with histories of consanguinity and segregated in over 10 affected family member s (Shahzad 2013). It has also been identified in 4/235612 chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7825 39587); however, this frequency is low enough to be consistent with a carrier fr equency for recessive Usher syndrome. The p.Lys420X nonsense variant leads to a premature termination codon at position 420, which is predicted to lead to a tru ncated or absent protein. Loss of MYO7A gene function is an established disease mechanism for autosomal recessive Usher syndrome. In summary, this variant meet s criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the predicted impact of the variant, homozygosity and compound zygosit y in affected individuals, segregation evidence, and low frequency in the genera l population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.94

GERP RS

4.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over