rs2955366

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016239.4(MYO15A):c.1899A>G(p.Pro633Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,543,570 control chromosomes in the GnomAD database, including 113,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14513 hom., cov: 31)

Exomes 𝑓: 0.36 ( 98680 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.111

Publications

20 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.09).

BP6

Variant 17-18120699-A-G is Benign according to our data. Variant chr17-18120699-A-G is described in ClinVar as Benign. ClinVar VariationId is 226778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.111 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.1899A>G	p.Pro633Pro	synonymous_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.1899A>G	p.Pro633Pro	synonymous_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1 link	n.1532A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.424

AC:

63952

AN:

150662

Hom.:

14479

Cov.:

show subpopulations

Gnomad AFR

AF:

0.523

Gnomad AMI

AF:

0.418

Gnomad AMR

AF:

0.468

Gnomad ASJ

AF:

0.416

Gnomad EAS

AF:

0.636

Gnomad SAS

AF:

0.705

Gnomad FIN

AF:

0.415

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.321

Gnomad OTH

AF:

0.405

GnomAD2 exomes

AF:

0.459

AC:

68279

AN:

148870

AF XY:

0.468

show subpopulations

Gnomad AFR exome

AF:

0.524

Gnomad AMR exome

AF:

0.501

Gnomad ASJ exome

AF:

0.420

Gnomad EAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.396

Gnomad NFE exome

AF:

0.326

Gnomad OTH exome

AF:

0.432

GnomAD4 exome

AF:

0.358

AC:

499011

AN:

1392804

Hom.:

98680

Cov.:

AF XY:

0.369

AC XY:

254271

AN XY:

689474

show subpopulations

African (AFR)

AF:

0.536

AC:

16181

AN:

30180

American (AMR)

AF:

0.493

AC:

17834

AN:

36202

Ashkenazi Jewish (ASJ)

AF:

0.421

AC:

10418

AN:

24766

East Asian (EAS)

AF:

0.655

AC:

23495

AN:

35878

South Asian (SAS)

AF:

0.701

AC:

56095

AN:

80034

European-Finnish (FIN)

AF:

0.383

AC:

14313

AN:

37374

Middle Eastern (MID)

AF:

0.453

AC:

2153

AN:

4758

European-Non Finnish (NFE)

AF:

0.309

AC:

335575

AN:

1085802

Other (OTH)

AF:

0.397

AC:

22947

AN:

57810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

19031

38062

57094

76125

95156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11350

22700

34050

45400

56750

<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:

0.425

AC:

64035

AN:

150766

Hom.:

14513

Cov.:

AF XY:

0.435

AC XY:

32017

AN XY:

73634

show subpopulations

African (AFR)

AF:

0.524

AC:

21518

AN:

41056

American (AMR)

AF:

0.469

AC:

7121

AN:

15182

Ashkenazi Jewish (ASJ)

AF:

0.416

AC:

1441

AN:

3462

East Asian (EAS)

AF:

0.637

AC:

3225

AN:

5066

South Asian (SAS)

AF:

0.705

AC:

3390

AN:

4806

European-Finnish (FIN)

AF:

0.415

AC:

4284

AN:

10330

Middle Eastern (MID)

AF:

0.390

AC:

113

AN:

290

European-Non Finnish (NFE)

AF:

0.321

AC:

21719

AN:

67580

Other (OTH)

AF:

0.405

AC:

846

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1739

3478

5217

6956

8695

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

598

1196

1794

2392

2990

<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:

0.361

Hom.:

3464

Bravo

AF:

0.427

Asia WGS

AF:

0.647

AC:

2223

AN:

3438

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro633Pro in Exon 02 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 42.4% (1017/2398) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2955366). -

Jan 20, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 09, 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. -

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 3

Benign:3

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 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. -

not provided

Benign:2

Feb 03, 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

1.1

(source)

DANN

Benign

0.26

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism (auto)

(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