chr17-18161408-C-T

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.9478C>T(p.Leu3160Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00823 in 1,614,082 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L3160L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0066 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0084 ( 68 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 4.83

Publications

25 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 (MetaRNN=0.01386866).

BP6

Variant 17-18161408-C-T is Benign according to our data. Variant chr17-18161408-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45773.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=2, Benign=4, Likely_benign=3}.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00665 (1012/152280) while in subpopulation NFE AF = 0.00822 (559/68026). AF 95% confidence interval is 0.00765. There are 5 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.9478C>T	p.Leu3160Phe	missense_variant	Exon 57 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.9481C>T	p.Leu3161Phe	missense_variant	Exon 55 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.9418C>T	p.Leu3140Phe	missense_variant	Exon 54 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.9478C>T	p.Leu3160Phe	missense_variant	Exon 57 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00666

AC:

1013

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00632

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00387

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00822

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00691

AC:

1723

AN:

249434

AF XY:

0.00694

show subpopulations

Gnomad AFR exome

AF:

0.00749

Gnomad AMR exome

AF:

0.00545

Gnomad ASJ exome

AF:

0.00864

Gnomad EAS exome

AF:

0.00289

Gnomad FIN exome

AF:

0.00302

Gnomad NFE exome

AF:

0.00844

Gnomad OTH exome

AF:

0.00973

GnomAD4 exome

AF:

0.00840

AC:

12279

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

5937

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.00729

AC:

244

AN:

33480

American (AMR)

AF:

0.00550

AC:

246

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26136

East Asian (EAS)

AF:

0.00612

AC:

243

AN:

39700

South Asian (SAS)

AF:

0.00649

AC:

560

AN:

86258

European-Finnish (FIN)

AF:

0.00321

AC:

171

AN:

53338

Middle Eastern (MID)

AF:

0.00936

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00905

AC:

10060

AN:

1112004

Other (OTH)

AF:

0.00818

AC:

494

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

835

1671

2506

3342

4177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00665

AC:

1012

AN:

152280

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00628

AC:

261

AN:

41564

American (AMR)

AF:

0.00497

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00387

AC:

AN:

5162

South Asian (SAS)

AF:

0.00622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00822

AC:

559

AN:

68026

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

194

243

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00715

Hom.:

Bravo

AF:

0.00716

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00680

AC:

ESP6500EA

AF:

0.00883

AC:

ExAC

AF:

0.00684

AC:

829

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00894

EpiControl

AF:

0.00848

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 17546645, 25792667, 27018795, 25262649, 24498627, 24130743, 20440071, 27375115, 25587757, 30245029) -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 23, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: BS2 -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:2Benign:1

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Molecular Diagnosis Center for Deafness

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2018

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:2

Oct 16, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Leu3160Phe in Exon 57 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.8% (54/6912) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs140029076). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.062

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;D;D;.;.;.;.;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.69

T;.;T;T;T;T;T;T

M_CAP

Pathogenic

0.33

MetaRNN

Benign

0.014

T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.5

.;M;M;.;.;.;.;.

PhyloP100

4.8

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

.;D;.;D;.;D;.;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0090

.;D;.;D;.;D;.;.

Sift4G

Benign

0.091

T;T;.;T;.;D;D;D

Polyphen

0.67

.;P;P;.;.;.;.;.

Vest4

0.45

MVP

0.87

ClinPred

0.038

GERP RS

1.4

Varity_R

0.20

gMVP

0.39

Mutation Taster

=50/50

(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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chr17-18161408-C-T

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