chr17-18163739-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_016239.4(MYO15A):c.9691-3C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,611,862 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

MYO15A
NM_016239.4 splice_region, intron

Scores

Splicing: ADA: 0.9869

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.43

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: Likely_benign. The variant received -4 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 17-18163739-C-A is Benign according to our data. Variant chr17-18163739-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45776.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
MYO15A	NM_016239.4 link	c.9691-3C>A	splice_region_variant, intron_variant	Intron 59 of 65	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3 link	c.9694-3C>A	splice_region_variant, intron_variant	Intron 57 of 63		XP_016880204.1
MYO15A	XM_017024714.3 link	c.9631-3C>A	splice_region_variant, intron_variant	Intron 56 of 62		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.9691-3C>A		splice_region_variant, intron_variant	Intron 59 of 65		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000313

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00127

AC:

310

AN:

245060

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.000199

Gnomad AMR exome

AF:

0.000964

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000951

Gnomad NFE exome

AF:

0.00108

Gnomad OTH exome

AF:

0.00284

GnomAD4 exome

AF:

0.00127

AC:

1857

AN:

1459496

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

913

AN XY:

725738

show subpopulations

African (AFR)

AF:

0.000210

AC:

AN:

33410

American (AMR)

AF:

0.000853

AC:

AN:

44540

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

266

AN:

26078

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00116

AC:

AN:

85672

European-Finnish (FIN)

AF:

0.0000751

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00119

AC:

1326

AN:

1110818

Other (OTH)

AF:

0.00191

AC:

115

AN:

60290

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

102

204

305

407

509

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:

0.00114

AC:

173

AN:

152366

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41590

American (AMR)

AF:

0.000914

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00166

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00163

AC:

111

AN:

68032

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.00180

Hom.:

Bravo

AF:

0.00103

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: BP4, BS2 -

Jul 08, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 26, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 27, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.9691-3C>A in exon 60 MYO15A: This variant has been identified by our laborato ry in 4 individuals with hearing loss, two of whom had pathogenic variants in di fferent genes that explained the hearing loss. The remaining two individuals wh o were heterozygous had either unilateral or significantly assymmetrical mixed h earing loss (mild in one ear, profound in the other), which is not consistent wi th a MYO15A-related hearing loss. It has not been reported in the literature. T his variant has been identified in several populations by the Exome Aggregation Consortium with the highest frequency of 0.2% (93/46340) in European chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs142996507). Given the relatively high frequency of this variant in the general population and the fact that it h as never been reported in trans with a pathogenic variant in MYO15A in an indivi dual with hearing loss, this variant is likely benign. -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

MYO15A-related disorder

Benign:1

Sep 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.90

PhyloP100

1.4

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.87

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