17-18166434-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BP7

The NM_016239.4(MYO15A):c.9861C>T(p.Gly3287Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000886 in 1,613,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -1.25

Publications

3 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_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-18166434-C-T is Pathogenic according to our data. Variant chr17-18166434-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 45777.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54). . Strength limited to SUPPORTING due to the PP5.

BP7

Synonymous conserved (PhyloP=-1.25 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.9861C>T	p.Gly3287Gly	synonymous_variant	Exon 61 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.9864C>T	p.Gly3288Gly	synonymous_variant	Exon 59 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.9801C>T	p.Gly3267Gly	synonymous_variant	Exon 58 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.9861C>T	p.Gly3287Gly	synonymous_variant	Exon 61 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000188

AC:

AN:

249412

AF XY:

0.000177

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00407

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000495

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727166

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00329

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53264

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1112006

Other (OTH)

AF:

0.000215

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000105

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.000316

Hom.:

Bravo

AF:

0.0000982

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:3

Apr 09, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MYO15A c.9861C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: One predict the variant weakens a cryptic 5' donor site. One predict the variant creates a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00019 in 249412 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MYO15A causing Autosomal Recessive Nonsyndromic Hearing Loss 3, allowing no conclusion about variant significance. c.9861C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 3 and has been identified as a founder change in Ashkenazi Jews (Brownstein_2020, Booth_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34733312, 33111345, 33398081, 36515421). ClinVar contains an entry for this variant (Variation ID: 45777). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 13, 2025

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The MYO15A c.9861C>T:p.G3287G variant has been detected in our study, in 2 Jewish Ashkenazi families, in compound heterozygosity with another known Ashkenazi MYO15A mutation: c.8183G>A:p.R2728H. Following immediate application of our findings in the genetics clinics in Israel, 5 additional families were detected with full segregation of this variant in compound heterozygosity with a known MYO15A deafness variant. Compound heterozygosity has not been detected in none if the 23 hearing members in these families. MYO15A c.9861C>T is predicted to lead to loss of splicing enhancer motifs by 4 of 6 HSF algorithms and to lead to gain of silencer motifs by 2 of 6 algorithms. Skipping of MYO16A exon 61 would lead to a message deletion of 161bp and a premature stop at codon 3266 of 3531. -

not provided

Pathogenic:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: PM3:Very Strong, PM2:Supporting, PS3:Supporting, BP4 -

Jul 03, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest that this variant results in aberrant splicing and "skipping" of exon 61 (PMID: 33398081); In silico analysis suggests that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 33398081, WangS2023[casereport], 33111345, 34733312, 36515421) -

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 3287 of the MYO15A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the MYO15A protein. This variant is present in population databases (rs372466080, gnomAD 0.4%). This variant has been observed in individual(s) with non-syndromic deafness (PMID: 33111345, 33398081, 34733312). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 33111345, 33398081, 34733312). ClinVar contains an entry for this variant (Variation ID: 45777). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 33398081). For these reasons, this variant has been classified as Pathogenic. -

MYO15A-related disorder

Pathogenic:1

Nov 29, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The MYO15A c.9861C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the homozygous and compound heterozygous states in patients with nonsyndromic hearing loss (Brownstein et al 2020. PubMed ID: 33111345; Hirsch et al 2021. PubMed ID: 33398081; Booth et al 2021. PubMed ID: 34733312). Functional in vitro studies have shown this variant results in exon skipping, a frameshift and premature termination (Hirsch et al 2021. PubMed ID: 33398081). This variant is reported in 0.41% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has been described as a pathogenic founder variant in this population (http://gnomad.broadinstitute.org/variant/17-18069748-C-T; Brownstein et al 2020. PubMed ID: 33111345). This variant is interpreted as likely pathogenic. -

Rare genetic deafness

Pathogenic:1

Oct 22, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

proposed classification - variant undergoing re-assessment, contact laboratory -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

0.93

(source)

DANN

Benign

0.64

PhyloP100

-1.3

Mutation Taster

=99/1

disease causing (ClinVar)

(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