rs2280777

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.4954C>T(p.Leu1652Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,613,386 control chromosomes in the GnomAD database, including 233,604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L1652L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.52 ( 20763 hom., cov: 32)

Exomes 𝑓: 0.54 ( 212841 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.24

Publications

33 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=-0.52).

BP6

Variant 17-18138193-C-T is Benign according to our data. Variant chr17-18138193-C-T is described in ClinVar as Benign. ClinVar VariationId is 226788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.4954C>T	p.Leu1652Leu	synonymous_variant	Exon 17 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.4954C>T	p.Leu1652Leu	synonymous_variant	Exon 17 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1
MYO15A	ENST00000646238.1 link	n.218C>T		non_coding_transcript_exon_variant	Exon 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78615

AN:

151956

Hom.:

20734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.447

Gnomad AMI

AF:

0.511

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.537

Gnomad OTH

AF:

0.510

GnomAD2 exomes

AF:

0.532

AC:

132499

AN:

249148

AF XY:

0.519

show subpopulations

Gnomad AFR exome

AF:

0.440

Gnomad AMR exome

AF:

0.652

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.595

Gnomad FIN exome

AF:

0.608

Gnomad NFE exome

AF:

0.524

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.536

AC:

783490

AN:

1461312

Hom.:

212841

Cov.:

AF XY:

0.530

AC XY:

385428

AN XY:

726992

show subpopulations

African (AFR)

AF:

0.440

AC:

14740

AN:

33478

American (AMR)

AF:

0.641

AC:

28651

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.545

AC:

14248

AN:

26136

East Asian (EAS)

AF:

0.593

AC:

23550

AN:

39698

South Asian (SAS)

AF:

0.379

AC:

32699

AN:

86254

European-Finnish (FIN)

AF:

0.611

AC:

32340

AN:

52936

Middle Eastern (MID)

AF:

0.416

AC:

2400

AN:

5768

European-Non Finnish (NFE)

AF:

0.542

AC:

602584

AN:

1111936

Other (OTH)

AF:

0.535

AC:

32278

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

22969

45937

68906

91874

114843

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17188

34376

51564

68752

85940

<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:

0.517

AC:

78676

AN:

152074

Hom.:

20763

Cov.:

AF XY:

0.519

AC XY:

38609

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.446

AC:

18505

AN:

41478

American (AMR)

AF:

0.576

AC:

8810

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.540

AC:

1871

AN:

3466

East Asian (EAS)

AF:

0.593

AC:

3066

AN:

5166

South Asian (SAS)

AF:

0.386

AC:

1861

AN:

4818

European-Finnish (FIN)

AF:

0.604

AC:

6389

AN:

10578

Middle Eastern (MID)

AF:

0.466

AC:

137

AN:

294

European-Non Finnish (NFE)

AF:

0.537

AC:

36488

AN:

67948

Other (OTH)

AF:

0.513

AC:

1083

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1954

3908

5863

7817

9771

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.528

Hom.:

80658

Bravo

AF:

0.514

Asia WGS

AF:

0.487

AC:

1696

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu1652Leu in Exon 17 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 47.4% (3316/6998) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2280777). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.8

(source)

DANN

Benign

0.58

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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