rs142293185

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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

Publications

11 publications found

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 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

MYO7A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 43305.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.5866G>A	p.Val1956Ile	missense_variant	Exon 43 of 49	ENST00000409709.9	NP_000251.3	Q13402-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MYO7A	ENST00000409709.9 link	c.5866G>A	p.Val1956Ile	missense_variant	Exon 43 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000458637.6 link	c.5752G>A	p.Val1918Ile	missense_variant	Exon 43 of 49	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.5719G>A	p.Val1907Ile	missense_variant	Exon 44 of 50	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.3292G>A	p.Val1098Ile	missense_variant	Exon 23 of 29	1		ENSP00000417017.2	H7C4D8
MYO7A	ENST00000670577.1 link	n.*464G>A		non_coding_transcript_exon_variant	Exon 26 of 32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000670577.1 link	n.*464G>A		3_prime_UTR_variant	Exon 26 of 32			ENSP00000499323.1	A0A590UJ94

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

GnomAD2 exomes

AF:

0.00398

AC:

987

AN:

248044

AF XY:

0.00400

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 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

African (AFR)

AF:

0.00126

AC:

AN:

33446

American (AMR)

AF:

0.00184

AC:

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

391

AN:

26114

East Asian (EAS)

AF:

0.000101

AC:

AN:

39688

South Asian (SAS)

AF:

0.00203

AC:

175

AN:

86092

European-Finnish (FIN)

AF:

0.00341

AC:

182

AN:

53364

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00452

AC:

5023

AN:

1110768

Other (OTH)

AF:

0.00403

AC:

243

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

263

527

790

1054

1317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00370

AC:

564

AN:

152318

Hom.:

Cov.:

AF XY:

0.00349

AC XY:

260

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

41572

American (AMR)

AF:

0.00399

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00249

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00282

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68022

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00481

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

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO7A: BS2 -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 12, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25558175, 23804846, 15121790) -

not specified

Benign:4

Nov 19, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 15, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 2

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Autosomal dominant nonsyndromic hearing loss 11

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Oct 03, 2017

Counsyl

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Usher syndrome type 1B

Benign:1

Nov 01, 2019

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

0.14

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

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;.;.;.

PhyloP100

3.9

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

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over