17-18121038-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA8423237/MONDO:0019497/005

Frequency

Genomes: 𝑓 0.015 ( 44 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 41 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:7

Conservation

PhyloP100: 0.105

Publications

2 publications found

Variant links:

Genes affected

MYO15A (HGNC:7594): (myosin XVA) This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

MYO15A Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BA1

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.2238G>T	p.Arg746Ser	missense_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.2238G>T	p.Arg746Ser	missense_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000583079.1 link	n.1871G>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2201

AN:

151052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0106

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.0126

GnomAD2 exomes

AF:

0.00195

AC:

213

AN:

109144

AF XY:

0.00153

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000326

Gnomad OTH exome

AF:

0.00365

GnomAD4 exome

AF:

0.00139

AC:

1884

AN:

1358612

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

839

AN XY:

670106

show subpopulations

African (AFR)

AF:

0.0450

AC:

1272

AN:

28242

American (AMR)

AF:

0.00399

AC:

135

AN:

33832

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24248

East Asian (EAS)

AF:

0.00

AC:

AN:

32786

South Asian (SAS)

AF:

0.0000913

AC:

AN:

76632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35260

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

4844

European-Non Finnish (NFE)

AF:

0.000214

AC:

228

AN:

1066214

Other (OTH)

AF:

0.00382

AC:

216

AN:

56554

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

110

219

329

438

548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.0146

AC:

2207

AN:

151160

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1037

AN XY:

73878

show subpopulations

African (AFR)

AF:

0.0483

AC:

2003

AN:

41436

American (AMR)

AF:

0.0106

AC:

161

AN:

15208

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3450

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10154

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000192

AC:

AN:

67630

Other (OTH)

AF:

0.0125

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

115

230

345

460

575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00944

Hom.:

Bravo

AF:

0.0169

ESP6500AA

AF:

0.0259

AC:

ESP6500EA

AF:

0.000403

AC:

ExAC

AF:

0.00126

AC:

Asia WGS

AF:

0.00272

AC:

AN:

3324

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Arg746Ser in Exon 02 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 2.6% (42/1612) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs79760961). -

Dec 18, 2017

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. -

Jul 08, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 22, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nonsyndromic genetic hearing loss

Benign:1

Jun 15, 2021

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The filtering allele frequency (the lower threshold of the 95% CI of 511/11092) of the p.Arg746Ser variant in the MYO15A gene is 4.27% for African chromosomes (including 8 homozygous observations) by gnomAD, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). Additionally, computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel : BA1, BP4. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.8

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.46

T;.;T

MetaRNN

Benign

0.0025

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.69

.;N;N

PhyloP100

0.10

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.75

.;N;.

REVEL

Benign

0.12

Sift

Uncertain

0.0080

.;D;.

Sift4G

Benign

0.081

T;T;.

Polyphen

0.29

.;B;B

Vest4

0.32

MutPred

0.36

Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);Gain of glycosylation at R746 (P = 0.0109);

MVP

0.54

ClinPred

0.0097

GERP RS

1.1

Varity_R

0.097

gMVP

0.34

Mutation Taster

=94/6

polymorphism

(source)

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

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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