NM_016239.4:c.9518-11T>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.9518-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,884 control chromosomes in the GnomAD database, including 29,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 2871 hom., cov: 33)

Exomes 𝑓: 0.18 ( 26151 hom. )

Consequence

MYO15A
NM_016239.4 intron

Scores

Splicing: ADA: 0.0001856

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.137

Publications

6 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 17-18162574-T-C is Benign according to our data. Variant chr17-18162574-T-C is described in ClinVar as Benign. ClinVar VariationId is 45775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.9518-11T>C	intron_variant	Intron 57 of 65	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.9521-11T>C	intron_variant	Intron 55 of 63		XP_016880204.1
MYO15A	XM_017024714.3 link	c.9458-11T>C	intron_variant	Intron 54 of 62		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.9518-11T>C		intron_variant	Intron 57 of 65		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28767

AN:

152100

Hom.:

2857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.147

Gnomad AMR

AF:

0.164

Gnomad ASJ

AF:

0.242

Gnomad EAS

AF:

0.00828

Gnomad SAS

AF:

0.171

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.209

GnomAD2 exomes

AF:

0.169

AC:

41433

AN:

245520

AF XY:

0.174

show subpopulations

Gnomad AFR exome

AF:

0.212

Gnomad AMR exome

AF:

0.103

Gnomad ASJ exome

AF:

0.237

Gnomad EAS exome

AF:

0.00452

Gnomad FIN exome

AF:

0.142

Gnomad NFE exome

AF:

0.204

Gnomad OTH exome

AF:

0.191

GnomAD4 exome

AF:

0.184

AC:

269281

AN:

1460664

Hom.:

26151

Cov.:

AF XY:

0.186

AC XY:

134874

AN XY:

726592

show subpopulations

African (AFR)

AF:

0.221

AC:

7380

AN:

33464

American (AMR)

AF:

0.113

AC:

5054

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.243

AC:

6347

AN:

26118

East Asian (EAS)

AF:

0.00280

AC:

111

AN:

39690

South Asian (SAS)

AF:

0.186

AC:

16075

AN:

86202

European-Finnish (FIN)

AF:

0.143

AC:

7570

AN:

53028

Middle Eastern (MID)

AF:

0.305

AC:

1759

AN:

5762

European-Non Finnish (NFE)

AF:

0.192

AC:

213608

AN:

1111404

Other (OTH)

AF:

0.189

AC:

11377

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

11561

23122

34682

46243

57804

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7272

14544

21816

29088

36360

<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:

0.189

AC:

28830

AN:

152220

Hom.:

2871

Cov.:

AF XY:

0.184

AC XY:

13705

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.212

AC:

8781

AN:

41510

American (AMR)

AF:

0.164

AC:

2508

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

841

AN:

3472

East Asian (EAS)

AF:

0.00830

AC:

AN:

5182

South Asian (SAS)

AF:

0.172

AC:

832

AN:

4828

European-Finnish (FIN)

AF:

0.146

AC:

1553

AN:

10614

Middle Eastern (MID)

AF:

0.259

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13613

AN:

67990

Other (OTH)

AF:

0.212

AC:

449

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

1200

2399

3599

4798

5998

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

314

628

942

1256

1570

<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:

0.198

Hom.:

579

Bravo

AF:

0.193

Asia WGS

AF:

0.108

AC:

374

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

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

9518-11T>C in Intron 57 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 20.7% (1381/6676) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs62073604). -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 14, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.2

(source)

DANN

Benign

0.61

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.10

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