chr17-18130805-A-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.4033A>T(p.Ile1345Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,605,052 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

MYO15A
NM_016239.4 missense, splice_region

Scores

Splicing: ADA: 0.01628

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 2.39

Publications

0 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=0.01732254).

BP6

Variant 17-18130805-A-T is Benign according to our data. Variant chr17-18130805-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198880.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00181 (264/145546) while in subpopulation NFE AF = 0.00341 (228/66920). AF 95% confidence interval is 0.00304. There are 0 homozygotes in GnomAd4. There are 121 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.4033A>T	p.Ile1345Leu	missense_variant, splice_region_variant	Exon 8 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.4033A>T	p.Ile1345Leu	missense_variant, splice_region_variant	Exon 8 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

264

AN:

145434

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000512

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00153

AC:

377

AN:

246486

AF XY:

0.00159

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000378

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.00326

AC:

4761

AN:

1459506

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2275

AN XY:

726164

show subpopulations

African (AFR)

AF:

0.000540

AC:

AN:

33328

American (AMR)

AF:

0.000314

AC:

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39418

South Asian (SAS)

AF:

0.00

AC:

AN:

86198

European-Finnish (FIN)

AF:

0.000604

AC:

AN:

53018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00413

AC:

4589

AN:

1110794

Other (OTH)

AF:

0.00169

AC:

102

AN:

60254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

227

454

682

909

1136

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

368

552

736

920

<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:

0.00181

AC:

264

AN:

145546

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

121

AN XY:

70726

show subpopulations

African (AFR)

AF:

0.000653

AC:

AN:

38268

American (AMR)

AF:

0.000412

AC:

AN:

14572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

4854

South Asian (SAS)

AF:

0.00

AC:

AN:

4536

European-Finnish (FIN)

AF:

0.000512

AC:

AN:

9774

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.00341

AC:

228

AN:

66920

Other (OTH)

AF:

0.00

AC:

AN:

2000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.00191

Hom.:

Bravo

AF:

0.00174

ESP6500AA

AF:

0.000487

AC:

ESP6500EA

AF:

0.00406

AC:

ExAC

AF:

0.00150

AC:

182

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 12, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MYO15A: PP3, BS2 -

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. -

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

Ile1345Leu in Exon 08 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (27/6778) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS). -

MYO15A-related disorder

Benign:1

Feb 21, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.28

.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.2

L;L

PhyloP100

2.4

PROVEAN

Benign

-0.71

N;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.0090

D;.

Vest4

0.46

MutPred

0.41

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.84

ClinPred

0.023

GERP RS

2.7

Varity_R

0.19

gMVP

0.34

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.016

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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