rs41298135

Positions:

• chr11-77158332-G-A
• chr11-77158332-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP2 BS3_Supporting BS1

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
• Clinical Significance: Likely benign reviewed by expert panel P:1 B:13
• Conservation: PhyloP100: 3.17

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.905G>A	p.Arg302His	missense_variant	9/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.905G>A	p.Arg302His	missense_variant	9/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.905G>A	p.Arg302His	missense_variant	9/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.872G>A	p.Arg291His	missense_variant	10/50	1		ENSP00000386635.2

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152168 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.00263 AC: 652 AN: 248024 Hom.: 3 AF XY: 0.00264 AC XY: 355 AN XY: 134674

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 SAS exome AF: 0.0000328

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.: 15 Cov.: 31 AF XY: 0.00292 AC XY: 2121 AN XY: 726640

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00315

Gnomad4 NFE exome AF: 0.00368

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.00189 AC XY: 141 AN XY: 74468

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00341

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00311 Hom.: 3

Bravo AF: 0.00180

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000233 AC: 1

ESP6500EA AF: 0.00271 AC: 23

ExAC AF: 0.00341 AC: 413

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Benign:13

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYO7A: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 30, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Usher syndrome type 1B Pathogenic:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1996	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2010	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

Likely 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 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

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

Usher syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Oct 22, 2018

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

Likely 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). 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 19, 2021

- -

Retinal dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;T;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.025	T;T;T;T
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;.;M;.
PrimateAI	Uncertain	0.60	T
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	T
GERP RS		5.7
Varity_R		0.75
gMVP		0.61

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

LitVar

Other links and lift over

dbSNP: rs41298135; hg19: chr11-76869378;