rs200641606

Positions:

• chr11-77181571-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000260.4(MYO7A):​c.2886G>C​(p.Gln962His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,613,212 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (3 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:5
• Conservation: PhyloP100: 1.39

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03781724).
• BP6: Variant 11-77181571-G-C is Benign according to our data. Variant chr11-77181571-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43194.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=10}. Variant chr11-77181571-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2886G>C	p.Gln962His	missense_variant	23/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2886G>C	p.Gln962His	missense_variant	23/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2886G>C	p.Gln962His	missense_variant	23/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2853G>C	p.Gln951His	missense_variant	24/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.429G>C	p.Gln143His	missense_variant	3/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.726G>C		non_coding_transcript_exon_variant	6/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000789 AC: 120 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000674 AC: 167 AN: 247660 Hom.: 0 AF XY: 0.000779 AC XY: 105 AN XY: 134864

Gnomad AFR exome AF: 0.0000651

Gnomad AMR exome AF: 0.000609

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00190

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000733

Gnomad OTH exome AF: 0.000832

GnomAD4 exome AF: 0.000901 AC: 1317 AN: 1460944 Hom.: 3 Cov.: 33 AF XY: 0.000956 AC XY: 695 AN XY: 726700

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000917

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000788 AC: 120 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62 AN XY: 74454

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00118

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000874 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000250 AC: 1

ESP6500EA AF: 0.000720 AC: 6

ExAC AF: 0.000712 AC: 86

Asia WGS AF: 0.00115 AC: 4 AN: 3476

EpiCase AF: 0.00115

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:6 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2017	The p.Gln962His variant (rs200641606) has been reported in one individual with a clinical diagnosis of Usher syndrome (Le Quesne Stabej 2012); however, inheritance and specific clinical information were not reported for this individual. The p.Gln962His variant is listed in the Genome Aggregation Database (gnomAD) browser with an overall allele frequency of 0.068% (identified in 187 out of 276,178 chromosomes; 0 homozygotes), and is classified as a variant of uncertain significance in ClinVar (Variant ID: 43194). The glutamine at codon 962 is moderately conserved considering 13 species (Alamut software v2.9.0), and computational analyses suggest that this variant affects the MYO7A protein structure/function (SIFT: damaging, PolyPhen2: possibly damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Gln962His variant cannot be determined with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 2024	Observed in patients with Usher syndrome or Meniere's disease in published literature; however, patient-level information was not available (PMID: 22135276, 30828346); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30828346, 34515852, 22135276) -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 19, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO7A: BS1:Supporting -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Usher syndrome type 1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, PP3_Supporting -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 09, 2016

p.Gln962His in exon 23 of MYO7A: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (39/15796) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs200641606). Although this variant has been reported in two individu als with hearing loss, in one individual two other pathogenic or likely pathogen ic variants were identified (LeQuesne Stabej 2012), and in the other individual a variant affecting the remaining copy of MYO7A was not identified. Therefore, given the frequency of this variant, it is likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;T;.;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.038	T;T;T;T;T;T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.4	M;.;M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D;.;D;D;.;D
REVEL	Uncertain	0.51
Sift	Benign	0.030	D;.;D;T;.;D
Sift4G	Uncertain	0.029	D;D;D;D;.;D
Polyphen		0.83	P;.;.;.;.;.
Vest4		0.72
MutPred		0.18		Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);Loss of solvent accessibility (P = 0.0238);.;.;.;
MVP		0.93
MPC		0.33
ClinPred		0.078	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.42

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: rs200641606; hg19: chr11-76892617;