chr11-77179894-G-A

Position:

• chr11-77179894-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The c.2527G>A variant in MYO7A is a missense variant predicted to cause substitution of valine by methionine at amino acid 843. The variant is present in 0.0006965 (23/22568) of South Asian alleles with a confidence interval of 95% in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.25, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. The variant has been reported in 6 probands, all of whom did not have clinical/phenotypic data, had other potentially pathogenic variants, or did not present with hearing loss (PMID:30755392, GeneDx, EGL Eurofins, Illumina). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the absence of ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA132253/MONDO:0019501/005

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00033 (1 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:13 B:2
• Conservation: PhyloP100: 0.565

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.2527G>A	p.Val843Met	missense_variant	21/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.2527G>A	p.Val843Met	missense_variant	21/49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.2527G>A	p.Val843Met	missense_variant	21/49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.2494G>A	p.Val832Met	missense_variant	22/50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.70G>A	p.Val24Met	missense_variant	1/29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.367G>A		non_coding_transcript_exon_variant	4/32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152248 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000456 AC: 63 AN: 138042 Hom.: 0 AF XY: 0.000534 AC XY: 40 AN XY: 74844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00102

Gnomad FIN exome AF: 0.000229

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00146

GnomAD4 exome AF: 0.000334 AC: 463 AN: 1387352 Hom.: 1 Cov.: 31 AF XY: 0.000364 AC XY: 249 AN XY: 684544

Gnomad4 AFR exome AF: 0.000127

Gnomad4 AMR exome AF: 0.000477

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000847

Gnomad4 FIN exome AF: 0.000610

Gnomad4 NFE exome AF: 0.000294

Gnomad4 OTH exome AF: 0.000571

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152366 Hom.: 0 Cov.: 34 AF XY: 0.000295 AC XY: 22 AN XY: 74500

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000341 Hom.: 0

Bravo AF: 0.000253

ESP6500AA AF: 0.000277 AC: 1

ESP6500EA AF: 0.000282 AC: 2

ExAC AF: 0.000337 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13 Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2024	Identified in one patient with multiple congenital anomalies and no reported hearing loss who also harbored variants in several other genes from a large cohort of patients who underwent WES (PMID: 30755392); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30755392) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 2 Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Usher syndrome type 1 Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Autosomal dominant nonsyndromic hearing loss 11 Uncertain:1 Benign:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 05, 2017

Variant classified as Uncertain Significance - Favor Benign. The p.Val843Met var iant in MYO7A has been previously identified by our laboratory in one Caucasian individual with hearing loss. It has also been identified in 0.1% (23/22644) of South Asian chromosomes and in 72/163744 of the total chromosomes with the highe st frequency of 0.1% (23/22644) in South Asian chromosomes by the Genome Aggrega tion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140559111). Com putational prediction tools and conservation analysis suggest that the p.Val843M et variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Val843Met variant is uncertain. ACMG/AMP Criteria applied: BP4 (Richards 2015 ). -

Usher syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Aug 03, 2022

The c.2527G>A variant in MYO7A is a missense variant predicted to cause substitution of valine by methionine at amino acid 843. The variant is present in 0.0006965 (23/22568) of South Asian alleles with a confidence interval of 95% in gnomAD v2.1.1. The computational predictor REVEL gives a score of 0.25, which is neither above nor below the thresholds predicting a damaging or benign impact on MYO7A function. The variant has been reported in 6 probands, all of whom did not have clinical/phenotypic data, had other potentially pathogenic variants, or did not present with hearing loss (PMID:30755392, GeneDx, EGL Eurofins, Illumina). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive Usher syndrome based on the absence of ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (ClinGen Hearing Loss VCEP specifications version 2; 7/20/2022). -

Usher syndrome type 1B Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 27, 2020

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T;.;.;.;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.037	T;T;T;T;T;T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	0.71	N;.;N;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.5	N;.;N;N;.;N
REVEL	Benign	0.25
Sift	Benign	0.051	T;.;D;D;.;D
Sift4G	Benign	0.18	T;T;T;T;.;D
Polyphen		0.30	B;.;.;.;.;.
Vest4		0.48
MVP		0.86
MPC		0.17
ClinPred		0.065	T
GERP RS		5.4
Varity_R		0.086
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs140559111; hg19: chr11-76890940; COSMIC: COSV68684538; COSMIC: COSV68684538;