rs861278

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.8460-15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,590 control chromosomes in the GnomAD database, including 124,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9348 hom., cov: 32)

Exomes 𝑓: 0.39 ( 115383 hom. )

Consequence

MYO15A
NM_016239.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.402

Publications

5 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=-0.8).

BP6

Variant 17-18156180-C-T is Benign according to our data. Variant chr17-18156180-C-T is described in ClinVar as Benign. ClinVar VariationId is 45769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.8460-15C>T	intron_variant	Intron 47 of 65	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.8463-15C>T	intron_variant	Intron 45 of 63		XP_016880204.1
MYO15A	XM_017024714.3 link	c.8400-15C>T	intron_variant	Intron 44 of 62		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.8460-15C>T		intron_variant	Intron 47 of 65		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.336

AC:

51026

AN:

151988

Hom.:

9346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.232

Gnomad AMI

AF:

0.431

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.396

Gnomad EAS

AF:

0.0869

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.422

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.417

Gnomad OTH

AF:

0.329

GnomAD2 exomes

AF:

0.334

AC:

83017

AN:

248462

AF XY:

0.334

show subpopulations

Gnomad AFR exome

AF:

0.223

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.408

Gnomad EAS exome

AF:

0.0908

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.411

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.388

AC:

567652

AN:

1461482

Hom.:

115383

Cov.:

AF XY:

0.383

AC XY:

278553

AN XY:

727044

show subpopulations

African (AFR)

AF:

0.227

AC:

7581

AN:

33470

American (AMR)

AF:

0.279

AC:

12458

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.400

AC:

10456

AN:

26124

East Asian (EAS)

AF:

0.101

AC:

4004

AN:

39698

South Asian (SAS)

AF:

0.215

AC:

18522

AN:

86240

European-Finnish (FIN)

AF:

0.438

AC:

23390

AN:

53392

Middle Eastern (MID)

AF:

0.309

AC:

1773

AN:

5746

European-Non Finnish (NFE)

AF:

0.421

AC:

467568

AN:

1111734

Other (OTH)

AF:

0.363

AC:

21900

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

19537

39074

58610

78147

97684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14126

28252

42378

56504

70630

<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:

0.336

AC:

51039

AN:

152108

Hom.:

9348

Cov.:

AF XY:

0.330

AC XY:

24508

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.232

AC:

9619

AN:

41472

American (AMR)

AF:

0.298

AC:

4553

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.396

AC:

1373

AN:

3470

East Asian (EAS)

AF:

0.0875

AC:

453

AN:

5176

South Asian (SAS)

AF:

0.212

AC:

1022

AN:

4820

European-Finnish (FIN)

AF:

0.422

AC:

4465

AN:

10592

Middle Eastern (MID)

AF:

0.357

AC:

105

AN:

294

European-Non Finnish (NFE)

AF:

0.417

AC:

28370

AN:

67966

Other (OTH)

AF:

0.325

AC:

686

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1704

3409

5113

6818

8522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

500

1000

1500

2000

2500

<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:

0.385

Hom.:

2166

Bravo

AF:

0.320

Asia WGS

AF:

0.162

AC:

565

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

8460-15C>T in Intron 47 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 40.0% (2731/6830) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs861278). -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

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. -

Sep 05, 2021

Genome-Nilou Lab

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

-0.80

CADD

Benign

3.8

(source)

DANN

Benign

0.68

PhyloP100

-0.40

Mutation Taster

=100/0

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