rs142293185

chr11-77208439-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000260.4(MYO7A):c.5866G>A(p.Val1956Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,612,528 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 18 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:12

Conservation

PhyloP100: 3.89

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009595692).

BP6

Variant 11-77208439-G-A is Benign according to our data. Variant chr11-77208439-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43305.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=3, Uncertain_significance=2}. Variant chr11-77208439-G-A is described in Lovd as [Benign]. Variant chr11-77208439-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0037 (564/152318) while in subpopulation NFE AF= 0.00501 (341/68022). AF 95% confidence interval is 0.00457. There are 2 homozygotes in gnomad4. There are 260 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO7A	NM_000260.4 linkuse as main transcript	c.5866G>A	p.Val1956Ile	missense_variant	43/49	ENST00000409709.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO7A	ENST00000409709.9 linkuse as main transcript	c.5866G>A	p.Val1956Ile	missense_variant	43/49	1	NM_000260.4		Q13402-1

Frequencies

GnomAD3 genomes

AF:

0.00371

AC:

564

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00398

AC:

987

AN:

248044

Hom.:

AF XY:

0.00400

AC XY:

539

AN XY:

134620

show subpopulations

Gnomad AFR exome

AF:

0.00130

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.0158

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.00220

Gnomad FIN exome

AF:

0.00302

Gnomad NFE exome

AF:

0.00522

Gnomad OTH exome

AF:

0.00481

GnomAD4 exome

AF:

0.00421

AC:

6144

AN:

1460210

Hom.:

Cov.:

AF XY:

0.00415

AC XY:

3015

AN XY:

726398

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00184

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00203

Gnomad4 FIN exome

AF:

0.00341

Gnomad4 NFE exome

AF:

0.00452

Gnomad4 OTH exome

AF:

0.00403

GnomAD4 genome

AF:

0.00370

AC:

564

AN:

152318

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00127

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.0167

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.00282

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00489

Hom.:

Bravo

AF:

0.00334

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00122

AC:

ESP6500EA

AF:

0.00297

AC:

ExAC

AF:

0.00432

AC:

523

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00447

EpiControl

AF:

0.00452

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2021	This variant is associated with the following publications: (PMID: 25558175, 23804846, 15121790) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO7A: BS2 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 15, 2012	Val1956Ile in Exon 43 of MYO7A: This variant is not expected to have clinical si gnificance because it has been identified in 0.3% (21/6834) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs142293185) and has been reported as benign (Street 2004, Le Quesne Stabej 2011). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 19, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Usher syndrome type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Autosomal dominant nonsyndromic hearing loss 11

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Usher syndrome type 1;C1838701:Autosomal recessive nonsyndromic hearing loss 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Counsyl

Oct 03, 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

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.;.;T

Eigen

Benign

0.088

Eigen_PC

Benign

0.067

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.045

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

2.0

M;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.82

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.24

T;T;T;T

Sift4G

Benign

0.42

T;T;T;T

Polyphen

0.94

P;.;.;.

Vest4

0.37

MVP

0.65

MPC

0.40

ClinPred

0.0082

GERP RS

3.4

Varity_R

0.12

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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