rs41298747

Positions:

chr11-77199663-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000260.4(MYO7A):c.4697C>T(p.Thr1566Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00537 in 1,612,946 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0050 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0054 ( 29 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.446

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006384641).

BP6

Variant 11-77199663-C-T is Benign according to our data. Variant chr11-77199663-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 43254.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-77199663-C-T is described in Lovd as [Benign]. Variant chr11-77199663-C-T is described in Lovd as [Likely_pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00502 (764/152328) while in subpopulation NFE AF= 0.00772 (525/68032). AF 95% confidence interval is 0.00717. There are 4 homozygotes in gnomad4. There are 357 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.4697C>T	p.Thr1566Met	missense_variant	35/49	ENST00000409709.9	NP_000251.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.4697C>T	p.Thr1566Met	missense_variant	35/49	1	NM_000260.4	ENSP00000386331		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.00502

AC:

764

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000916

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00734

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00772

Gnomad OTH

AF:

0.00766

GnomAD3 exomes

AF:

0.00499

AC:

1230

AN:

246704

Hom.:

AF XY:

0.00488

AC XY:

654

AN XY:

134134

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00239

Gnomad ASJ exome

AF:

0.0130

Gnomad EAS exome

AF:

0.000278

Gnomad SAS exome

AF:

0.00119

Gnomad FIN exome

AF:

0.00692

Gnomad NFE exome

AF:

0.00697

Gnomad OTH exome

AF:

0.00651

GnomAD4 exome

AF:

0.00540

AC:

7890

AN:

1460618

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

3893

AN XY:

726520

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00269

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00601

Gnomad4 NFE exome

AF:

0.00595

Gnomad4 OTH exome

AF:

0.00522

GnomAD4 genome

AF:

0.00502

AC:

764

AN:

152328

Hom.:

Cov.:

AF XY:

0.00479

AC XY:

357

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00734

Gnomad4 NFE

AF:

0.00772

Gnomad4 OTH

AF:

0.00758

Alfa

AF:

0.00677

Hom.:

Bravo

AF:

0.00422

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000958

AC:

ESP6500EA

AF:

0.00701

AC:

ExAC

AF:

0.00455

AC:

551

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00703

EpiControl

AF:

0.00688

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	MYO7A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2019	This variant is associated with the following publications: (PMID: 26969326, 25262649, 16679490, 22681893, 22952768, 12112664, 30245029) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 03, 2010	Thr1566Met in exon 35 of MYO7A: This variant has been reported in the literature (Cremers 2007, Najera 2002, Roux 2006) and in dbSNP (rs41298747). It is not exp ected to have clinical significance due to a common occurrence in controls and t he fact that the Met (methionine) variant at position 1566 is present in other m ammalian species including rat and mouse. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 30, 2015	- -

Usher syndrome type 1

Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Usher syndrome 1B, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -
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 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

Usher syndrome type 1B

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.22

T;.;.;T

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.85

D;D;D;T

MetaRNN

Benign

0.0064

T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;.;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.41

N;N;N;N

REVEL

Benign

0.073

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.12

T;T;T;T

Polyphen

0.66

P;.;.;.

Vest4

0.10

MVP

0.75

MPC

0.089

ClinPred

0.0051

GERP RS

-1.9

Varity_R

0.017

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over