17-18173861-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.10431T>C(p.Tyr3477Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,820 control chromosomes in the GnomAD database, including 450,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 46714 hom., cov: 34)

Exomes 𝑓: 0.74 ( 404091 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.791

Publications

26 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:

ENSG00000266677 (HGNC:):

ENSG00000266677 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 17-18173861-T-C is Benign according to our data. Variant chr17-18173861-T-C is described in ClinVar as Benign. ClinVar VariationId is 45744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.10431T>C	p.Tyr3477Tyr	synonymous_variant	Exon 65 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.10434T>C	p.Tyr3478Tyr	synonymous_variant	Exon 63 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.10371T>C	p.Tyr3457Tyr	synonymous_variant	Exon 62 of 63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.10431T>C	p.Tyr3477Tyr	synonymous_variant	Exon 65 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.779

AC:

118554

AN:

152146

Hom.:

46649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.802

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.773

GnomAD2 exomes

AF:

0.734

AC:

181585

AN:

247468

AF XY:

0.724

show subpopulations

Gnomad AFR exome

AF:

0.871

Gnomad AMR exome

AF:

0.784

Gnomad ASJ exome

AF:

0.809

Gnomad EAS exome

AF:

0.639

Gnomad FIN exome

AF:

0.749

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.753

GnomAD4 exome

AF:

0.742

AC:

1083874

AN:

1461556

Hom.:

404091

Cov.:

AF XY:

0.736

AC XY:

535235

AN XY:

727092

show subpopulations

African (AFR)

AF:

0.878

AC:

29405

AN:

33480

American (AMR)

AF:

0.783

AC:

34994

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.808

AC:

21124

AN:

26136

East Asian (EAS)

AF:

0.643

AC:

25523

AN:

39700

South Asian (SAS)

AF:

0.589

AC:

50800

AN:

86258

European-Finnish (FIN)

AF:

0.752

AC:

39954

AN:

53110

Middle Eastern (MID)

AF:

0.766

AC:

4416

AN:

5768

European-Non Finnish (NFE)

AF:

0.748

AC:

832325

AN:

1111994

Other (OTH)

AF:

0.751

AC:

45333

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18388

36776

55164

73552

91940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20292

40584

60876

81168

101460

<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:

0.779

AC:

118680

AN:

152264

Hom.:

46714

Cov.:

AF XY:

0.775

AC XY:

57671

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.874

AC:

36333

AN:

41568

American (AMR)

AF:

0.775

AC:

11860

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.802

AC:

2784

AN:

3470

East Asian (EAS)

AF:

0.641

AC:

3316

AN:

5172

South Asian (SAS)

AF:

0.586

AC:

2831

AN:

4834

European-Finnish (FIN)

AF:

0.747

AC:

7909

AN:

10592

Middle Eastern (MID)

AF:

0.772

AC:

227

AN:

294

European-Non Finnish (NFE)

AF:

0.753

AC:

51192

AN:

68016

Other (OTH)

AF:

0.772

AC:

1631

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1350

2700

4050

5400

6750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

862

1724

2586

3448

4310

<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:

0.761

Hom.:

119180

Bravo

AF:

0.787

Asia WGS

AF:

0.607

AC:

2113

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.734

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Tyr3477Tyr in Exon 65 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 24.0% (1601/6668) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854800). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.10

(source)

DANN

Benign

0.52

PhyloP100

-0.79

Mutation Taster

=95/5

polymorphism (auto)

(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