rs41298135

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP2BS3_SupportingBS1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the c.905G>A (p.Arg302His) variant in the MYO7A gene is 0.4% for European chromosomes by gnomAD (587/126276 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). While this variant has been reported in several individuals with Usher syndrome, in 2 individuals it was identified in cis with another pathogenic MYO7A variant (BP2; PMID 8900236). This variant has also been reported in at least 2 additional individuals with Usher syndrome who had alternate genetic etiologies identified (PMID:25468891). In addition, in vitro functional evidence from one study suggests that the Arg302His variant had little effect on motor activity of MYO7A (BS3_Supporting PMID:18700726). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP2, BS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132454/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 15 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel P:1B:13

Conservation

PhyloP100: 3.17

Publications

28 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 2
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, G2P
Usher syndrome type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia
Usher syndrome type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal dominant nonsyndromic hearing loss 11
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Usher syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP2

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.905G>A	p.Arg302His	missense_variant	Exon 9 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.905G>A	p.Arg302His	missense_variant	Exon 9 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.905G>A	p.Arg302His	missense_variant	Exon 9 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.872G>A	p.Arg291His	missense_variant	Exon 10 of 50	1		ENSP00000386635.2	Q13402-8

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00264

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00240

GnomAD2 exomes

AF:

0.00263

AC:

652

AN:

248024

AF XY:

0.00264

show subpopulations

Gnomad AFR exome

AF:

0.000713

Gnomad AMR exome

AF:

0.000349

Gnomad ASJ exome

AF:

0.000598

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00481

Gnomad OTH exome

AF:

0.00299

GnomAD4 exome

AF:

0.00304

AC:

4440

AN:

1460784

Hom.:

Cov.:

AF XY:

0.00292

AC XY:

2121

AN XY:

726640

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33462

American (AMR)

AF:

0.000403

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.000766

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86146

European-Finnish (FIN)

AF:

0.00315

AC:

167

AN:

53068

Middle Eastern (MID)

AF:

0.000868

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00368

AC:

4085

AN:

1111524

Other (OTH)

AF:

0.00207

AC:

125

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

234

468

701

935

1169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

304

456

608

760

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00202

AC:

307

AN:

152286

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.000794

AC:

AN:

41566

American (AMR)

AF:

0.000392

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00264

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00341

AC:

232

AN:

68014

Other (OTH)

AF:

0.00237

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00303

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.00271

AC:

ExAC

AF:

0.00341

AC:

413

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1Benign:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 30, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO7A: BS2 -

Usher syndrome type 1B

Pathogenic:1Benign:1

Nov 01, 1996

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 16, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 06, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been identified in 4.2% of controls(rs41298135) and functional studies do not show an impact to protein function (Watanabe 2008). -

Autosomal recessive nonsyndromic hearing loss 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant nonsyndromic hearing loss 11

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Usher syndrome

Benign:1

Oct 22, 2018

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency of the c.905G>A (p.Arg302His) variant in the MYO7A gene is 0.4% for European chromosomes by gnomAD (587/126276 with 95% CI), which is a high enough frequency to be classified as likely benign based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BS1). While this variant has been reported in several individuals with Usher syndrome, in 2 individuals it was identified in cis with another pathogenic MYO7A variant (BP2; PMID 8900236). This variant has also been reported in at least 2 additional individuals with Usher syndrome who had alternate genetic etiologies identified (PMID: 25468891). In addition, in vitro functional evidence from one study suggests that the Arg302His variant had little effect on motor activity of MYO7A (BS3_Supporting PMID: 18700726). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BS1, BP2, BS3_Supporting. -

Usher syndrome type 1

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Benign:1

Nov 19, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Benign:1

Jan 01, 2008

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.86

D;T;.;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.025

T;T;T;T

MetaSVM

Pathogenic

0.81

MutationAssessor

Uncertain

2.6

M;.;M;.

PhyloP100

3.2

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-4.3

D;.;D;D

REVEL

Pathogenic

0.67

Sift

Uncertain

0.0020

D;.;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.70

MVP

0.96

MPC

0.35

ClinPred

0.025

GERP RS

5.7

Varity_R

0.75

gMVP

0.61

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over