11-77201591-A-T

Variant names:

• chr11-77201591-A-T
• rs2276288
• NM_000260.4:c.4996A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000260.4(MYO7A):​c.4996A>T​(p.Ser1666Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 1,613,536 control chromosomes in the GnomAD database, including 246,230 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1666T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (26742 hom., cov: 31)
  • Exomes 𝑓: 0.54 (219488 hom.)
• Consequence: MYO7A NM_000260.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 2.52
• Publications: 51 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.6471216E-6).
• BP6: Variant 11-77201591-A-T is Benign according to our data. Variant chr11-77201591-A-T is described in ClinVar as Benign. ClinVar VariationId is 43269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.681 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4	c.4996A>T	p.Ser1666Cys	missense_variant	Exon 36 of 49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9	c.4996A>T	p.Ser1666Cys	missense_variant	Exon 36 of 49	1	NM_000260.4	ENSP00000386331.3
MYO7A	ENST00000458637.6	c.4882A>T	p.Ser1628Cys	missense_variant	Exon 36 of 49	1		ENSP00000392185.2
MYO7A	ENST00000409619.6	c.4849A>T	p.Ser1617Cys	missense_variant	Exon 37 of 50	1		ENSP00000386635.2
MYO7A	ENST00000458169.2	c.2422A>T	p.Ser808Cys	missense_variant	Exon 16 of 29	1		ENSP00000417017.2
MYO7A	ENST00000670577.1	n.2836A>T		non_coding_transcript_exon_variant	Exon 19 of 32			ENSP00000499323.1

Frequencies

GnomAD3 genomes AF: 0.587 AC: 89174 AN: 151850 Hom.: 26687 Cov.: 31

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.628

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.348

Gnomad FIN AF: 0.627

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.546

Gnomad OTH AF: 0.584

GnomAD2 exomes AF: 0.550 AC: 136951 AN: 249010 AF XY: 0.535

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.671

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.550

Gnomad OTH exome AF: 0.524

GnomAD4 exome AF: 0.544 AC: 795340 AN: 1461568 Hom.: 219488 Cov.: 63 AF XY: 0.538 AC XY: 390875 AN XY: 727064

African (AFR) AF: 0.685 AC: 22926 AN: 33480

American (AMR) AF: 0.664 AC: 29693 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 11335 AN: 26134

East Asian (EAS) AF: 0.472 AC: 18756 AN: 39696

South Asian (SAS) AF: 0.372 AC: 32043 AN: 86252

European-Finnish (FIN) AF: 0.625 AC: 33333 AN: 53336

Middle Eastern (MID) AF: 0.446 AC: 2573 AN: 5766

European-Non Finnish (NFE) AF: 0.551 AC: 612747 AN: 1111822

Other (OTH) AF: 0.529 AC: 31934 AN: 60366

GnomAD4 genome AF: 0.588 AC: 89296 AN: 151968 Hom.: 26742 Cov.: 31 AF XY: 0.588 AC XY: 43660 AN XY: 74228

African (AFR) AF: 0.687 AC: 28504 AN: 41474

American (AMR) AF: 0.629 AC: 9613 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1531 AN: 3468

East Asian (EAS) AF: 0.472 AC: 2421 AN: 5134

South Asian (SAS) AF: 0.348 AC: 1679 AN: 4818

European-Finnish (FIN) AF: 0.627 AC: 6614 AN: 10550

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.546 AC: 37119 AN: 67924

Other (OTH) AF: 0.582 AC: 1228 AN: 2110

Alfa AF: 0.544 Hom.: 17241

Bravo AF: 0.596

TwinsUK AF: 0.562 AC: 2085

ALSPAC AF: 0.552 AC: 2126

ESP6500AA AF: 0.681 AC: 2919

ESP6500EA AF: 0.543 AC: 4591

ExAC AF: 0.543 AC: 65799

Asia WGS AF: 0.435 AC: 1515 AN: 3478

EpiCase AF: 0.541

EpiControl AF: 0.539

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 08, 2007

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 22, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 22, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25342930, 19320733, 21569298)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive nonsyndromic hearing loss 2 Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Autosomal dominant nonsyndromic hearing loss 11 Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Usher syndrome type 1 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome type 1B Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.042
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.078
DEOGEN2	Benign	0.21	T;.;.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.13	T;T;T;T
MetaRNN	Benign	0.0000066	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.6	N;.;.;.
PhyloP100		2.5
PrimateAI	Benign	0.40	T
PROVEAN	Benign	5.5	N;N;N;N
REVEL	Benign	0.048
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.86	T;T;T;T
Vest4		0.23
ClinPred		0.0031	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.050
gMVP		0.32
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276288; hg19: chr11-76912636; COSMIC: COSV68684648; COSMIC: COSV68684648;