rs2276288

chr11-77201591-A-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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. S1666I) 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:12
• Conservation: PhyloP100: 2.52

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 43269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77201591-A-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MYO7A	NM_000260.4	c.4996A>T	p.Ser1666Cys	missense_variant	36/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9	c.4996A>T	p.Ser1666Cys	missense_variant	36/49	1	NM_000260.4

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

GnomAD3 exomes AF: 0.550 AC: 136951 AN: 249010 Hom.: 38891 AF XY: 0.535 AC XY: 72299 AN XY: 135100

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 SAS exome AF: 0.366

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

Gnomad4 AFR exome AF: 0.685

Gnomad4 AMR exome AF: 0.664

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.472

Gnomad4 SAS exome AF: 0.372

Gnomad4 FIN exome AF: 0.625

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.529

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

Gnomad4 AFR AF: 0.687

Gnomad4 AMR AF: 0.629

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.472

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.627

Gnomad4 NFE AF: 0.546

Gnomad4 OTH AF: 0.582

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 08, 2007	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2014	- -

Autosomal recessive nonsyndromic hearing loss 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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 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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Usher syndrome type 1 Benign:2

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25342930, 19320733, 21569298) -

Usher syndrome type 1B Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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;.;.;.
MutationTaster	Benign	1.0	P;P;P
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
MPC		0.082
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

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