rs368341987

Positions:

chr11-77179843-G-A

Variant summary

Our verdict is Uncertain significance. Variant got -4 ACMG points: 4P and 8B. PM3PP1PP4BA1

This summary comes from the ClinGen Evidence Repository: The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA180669/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.00042 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00071 ( 3 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:2U:11B:1O:1

Conservation

PhyloP100: 8.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got -4 ACMG points.

PM3

PP1

PP4

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.2476G>A	p.Ala826Thr	missense_variant	21/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.2476G>A	p.Ala826Thr	missense_variant	21/49	1	NM_000260.4		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00661

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00121

AC:

170

AN:

139996

Hom.:

AF XY:

0.00162

AC XY:

123

AN XY:

75716

show subpopulations

Gnomad AFR exome

AF:

0.000292

Gnomad AMR exome

AF:

0.0000816

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000939

Gnomad SAS exome

AF:

0.00650

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000338

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000711

AC:

989

AN:

1390456

Hom.:

Cov.:

AF XY:

0.000869

AC XY:

596

AN XY:

686182

show subpopulations

Gnomad4 AFR exome

AF:

0.000158

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000559

Gnomad4 SAS exome

AF:

0.00597

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000427

Gnomad4 OTH exome

AF:

0.000708

GnomAD4 genome

AF:

0.000420

AC:

AN:

152374

Hom.:

Cov.:

AF XY:

0.000523

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00662

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000419

Hom.:

Bravo

AF:

0.000329

ESP6500AA

AF:

0.000527

AC:

ESP6500EA

AF:

0.000129

AC:

ExAC

AF:

0.000974

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:11Benign:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as a variant of uncertain significance by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000927011.1; Oza et al., 2018); This variant is associated with the following publications: (PMID: 18181211, 23770805, 22135276, 33671976, 9382091, 27460420, 31479088, 29490346, 30311386, 30245029, 31456290, 30881389) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2022	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 826 of the MYO7A protein (p.Ala826Thr). This variant is present in population databases (rs368341987, gnomAD 0.6%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with Usher syndrome (PMID: 9382091, 29490346). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 177732). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MYO7A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Usher syndrome type 1

Pathogenic:1Uncertain:2

Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 24, 2021	NM_000260.3(MYO7A):c.2476G>A(A826T) is a missense variant classified as a variant of uncertain significance in the context of MYO7A-related disorders. A826T has been observed in cases with relevant disease (PMID: 9382091, 18181211, 22135276, 27460420, 29490346, 23770805, 30881389). Functional assessments of this variant are not available in the literature. A826T has been observed in population frequency databases (gnomAD: SAS 0.65%). In summary, there is insufficient evidence to classify NM_000260.3(MYO7A):c.2476G>A(A826T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

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

Uncertain:1Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 03, 2022	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 01/15/2018 by GTR ID Blueprint Genetics. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

MYO7A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The MYO7A c.2476G>A (p.Ala826Thr) missense variant has been reported in six studies in which it is found in a total of 19 patients with Usher syndrome including in 13 in a homozygous state, in five in a compound heterozygous state and in one in a heterozygous state (Adato et al. 1997; Riazuddin et al. 2008; Le Quesne Stabej et al. 2012; Shahzad et al. 2013; Vona et al. 2014; Bonnet et al. 2016). The p.Ala826Thr variant is present in a heterozygous state in two of 1214 control chromosomes and is reported at a frequency of 0.01471 in the Indian Telugu from the UK population of the 1000 Genomes project. The p.Ala826Thr variant is described as being located in the neck of the MYO7A protein within a motif whose sequence matches the consensus sequence of calmodulin-binding IQ motifs and is expected to impair the calmodulin chain-binding function of the protein. Based on the evidence, the p.Ala826Thr is classified as pathogenic for Usher Syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 03, 2017

proposed classification - variant undergoing re-assessment, contact laboratory -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Usher syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Jan 18, 2023

The variant NM_000260.4:c.2476G>A in MYO7A is a missense variant predicted to cause substitution of alanine by threonine at amino acid 826 (p.Ala826Thr). The filtering allele frequency of the variant is 0.55% for South Asian chromosomes by gnomAD, including 1 homozygous observation (144/22680 with 95% CI), meeting BA1 criteria. The REVEL computational prediction analysis tool produced a score of 0.54, which meets neither PP3 nor BP4 criteria. This variant has been detected in 2 patients with Usher syndrome in trans with pathogenic variants, and has been observed as homozygous in at least 9 cases (PM3; PMID:27460420, 29490346, 23770805, 22135276, 18181211, 9382091). The evidence originally met PM3_Strong criteria, however was downgraded to PM3 by the VCEP due to the high filtering allele frequency of the variant. The variant has also been reported to segregate with Usher syndrome in at least 12 family members (PP1_Strong; 23770805, 9382091). In most of these cases, the patients were documented to have both hearing loss and retinitis pigmentosa (PP4; PMID:27460420, 29490346, 23770805, 22135276, 9382091). In summary, the variant meets criteria to be classified as uncertain significance for AR Usher syndrome. ACMG/AMP criteria met, as specified by the ClinGen Hearing Loss VCEP: BA1, PM3, PP1_Strong, PP4 (ClinGen Hearing Loss VCEP specifications version 2; 1/18/2023). -

Usher syndrome type 1B

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Autosomal dominant nonsyndromic hearing loss 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;T;.;.;.;T

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D;D;D;T;D

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Uncertain

0.029

MutationAssessor

Benign

1.0

L;.;L;.;.;.

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.5

D;.;N;N;.;N

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

D;.;D;D;.;D

Sift4G

Uncertain

0.0090

D;D;D;D;.;D

Polyphen

0.65

P;.;.;.;.;.

Vest4

0.50

MVP

0.92

MPC

0.15

ClinPred

0.059

GERP RS

4.5

Varity_R

0.51

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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