rs150128469

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.5133+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,610,008 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 16 hom. )

Consequence

MYO15A
NM_016239.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.440

Publications

1 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 17-18138951-A-G is Benign according to our data. Variant chr17-18138951-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178442.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (324/152330) while in subpopulation NFE AF = 0.00276 (188/68032). AF 95% confidence interval is 0.00244. There are 1 homozygotes in GnomAd4. There are 140 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.5133+15A>G		intron_variant	Intron 18 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.5133+15A>G		intron_variant	Intron 18 of 65		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000646238.1 link	n.397+15A>G		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.00213

AC:

324

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00276

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00265

AC:

637

AN:

240162

AF XY:

0.00272

show subpopulations

Gnomad AFR exome

AF:

0.000758

Gnomad AMR exome

AF:

0.00161

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000483

Gnomad NFE exome

AF:

0.00331

Gnomad OTH exome

AF:

0.00307

GnomAD4 exome

AF:

0.00299

AC:

4359

AN:

1457678

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2198

AN XY:

724712

show subpopulations

African (AFR)

AF:

0.000658

AC:

AN:

33442

American (AMR)

AF:

0.00195

AC:

AN:

44148

Ashkenazi Jewish (ASJ)

AF:

0.0191

AC:

497

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.000947

AC:

AN:

85506

European-Finnish (FIN)

AF:

0.0000378

AC:

AN:

52928

Middle Eastern (MID)

AF:

0.00540

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00306

AC:

3396

AN:

1109974

Other (OTH)

AF:

0.00405

AC:

244

AN:

60258

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

245

491

736

982

1227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

134

268

402

536

670

<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:

0.00213

AC:

324

AN:

152330

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41572

American (AMR)

AF:

0.000980

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00276

AC:

188

AN:

68032

Other (OTH)

AF:

0.00378

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00506

Hom.:

Bravo

AF:

0.00238

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: BS2 -

Jun 16, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

5133+15A>G in Intron 18 of MYO15A: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 0.4% (26/6846) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs150128469). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.017

(source)

DANN

Benign

0.29

PhyloP100

-0.44

Mutation Taster

=100/0

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