rs111033183

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000260.4(MYO7A):c.4589C>T(p.Ser1530Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0043 in 1,517,142 control chromosomes in the GnomAD database, including 215 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1530S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 120 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 95 hom. )

Consequence

MYO7A
NM_000260.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.26

Publications

7 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002766192).

BP6

Variant 11-77199555-C-T is Benign according to our data. Variant chr11-77199555-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO7A	NM_000260.4 link	c.4589C>T	p.Ser1530Leu	missense_variant	Exon 35 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.4589C>T	p.Ser1530Leu	missense_variant	Exon 35 of 49	1	NM_000260.4	ENSP00000386331.3	Q13402-1
MYO7A	ENST00000670577.1 link	n.2429C>T		non_coding_transcript_exon_variant	Exon 18 of 32			ENSP00000499323.1	A0A590UJ94
MYO7A	ENST00000458637.6 link	c.4569-94C>T		intron_variant	Intron 34 of 48	1		ENSP00000392185.2	Q13402-2
MYO7A	ENST00000409619.6 link	c.4536-94C>T		intron_variant	Intron 35 of 49	1		ENSP00000386635.2	Q13402-8
MYO7A	ENST00000458169.2 link	c.2112-94C>T		intron_variant	Intron 14 of 28	1		ENSP00000417017.2	H7C4D8

Frequencies

GnomAD3 genomes

AF:

0.0220

AC:

3344

AN:

152216

Hom.:

119

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0755

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.00566

AC:

803

AN:

141834

AF XY:

0.00461

show subpopulations

Gnomad AFR exome

AF:

0.0771

Gnomad AMR exome

AF:

0.00478

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000287

Gnomad OTH exome

AF:

0.00402

GnomAD4 exome

AF:

0.00232

AC:

3172

AN:

1364808

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

1383

AN XY:

667262

show subpopulations

African (AFR)

AF:

0.0783

AC:

2450

AN:

31286

American (AMR)

AF:

0.00531

AC:

180

AN:

33902

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23108

East Asian (EAS)

AF:

0.00

AC:

AN:

35712

South Asian (SAS)

AF:

0.000202

AC:

AN:

74122

European-Finnish (FIN)

AF:

0.0000632

AC:

AN:

47454

Middle Eastern (MID)

AF:

0.00711

AC:

AN:

4926

European-Non Finnish (NFE)

AF:

0.000188

AC:

199

AN:

1057892

Other (OTH)

AF:

0.00514

AC:

290

AN:

56406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

167

335

502

670

837

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0220

AC:

3352

AN:

152334

Hom.:

120

Cov.:

AF XY:

0.0214

AC XY:

1592

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0755

AC:

3140

AN:

41582

American (AMR)

AF:

0.0108

AC:

165

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.0142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

153

306

459

612

765

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.00866

Hom.:

Bravo

AF:

0.0244

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0853

AC:

118

ESP6500EA

AF:

0.000314

AC:

ExAC

AF:

0.00435

AC:

504

Asia WGS

AF:

0.00664

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 06, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is not expected to have clinical significance because it has been i dentified in 3/17 (17.6%) Black probands in our lab, and as a homozygous variant in 2 individuals (Usher UMD), one of whom was homozygous for pathogenic MYO7A n onsense variant. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 28, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 03, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 15, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Autosomal recessive nonsyndromic hearing loss 2

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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 1B

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.0

PhyloP100

2.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.50

REVEL

Uncertain

0.33

Sift

Benign

0.34

Sift4G

Benign

0.31

Polyphen

0.0

Vest4

0.42

MVP

0.82

MPC

0.075

ClinPred

0.0075

GERP RS

2.2

Varity_R

0.050

gMVP

0.36

Mutation Taster

=95/5

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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