rs854778

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5826-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.734 in 1,610,714 control chromosomes in the GnomAD database, including 436,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.75 ( 43442 hom., cov: 30)

Exomes 𝑓: 0.73 ( 393105 hom. )

Consequence

MYO15A
NM_016239.4 intron

Scores

Splicing: ADA: 0.00001800

Clinical Significance

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

Conservation

PhyloP100: 0.446

Publications

15 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=-0.9).

BP6

Variant 17-18142744-A-C is Benign according to our data. Variant chr17-18142744-A-C is described in ClinVar as Benign. ClinVar VariationId is 45751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.5826-12A>C		intron_variant	Intron 24 of 65	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.5826-12A>C		intron_variant	Intron 24 of 65		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.753

AC:

114275

AN:

151696

Hom.:

43374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.656

Gnomad AMR

AF:

0.762

Gnomad ASJ

AF:

0.800

Gnomad EAS

AF:

0.601

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.752

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.745

Gnomad OTH

AF:

0.758

GnomAD2 exomes

AF:

0.717

AC:

175518

AN:

244836

AF XY:

0.707

show subpopulations

Gnomad AFR exome

AF:

0.796

Gnomad AMR exome

AF:

0.768

Gnomad ASJ exome

AF:

0.806

Gnomad EAS exome

AF:

0.600

Gnomad FIN exome

AF:

0.753

Gnomad NFE exome

AF:

0.737

Gnomad OTH exome

AF:

0.736

GnomAD4 exome

AF:

0.732

AC:

1067674

AN:

1458900

Hom.:

393105

Cov.:

AF XY:

0.726

AC XY:

527027

AN XY:

725620

show subpopulations

African (AFR)

AF:

0.809

AC:

27055

AN:

33446

American (AMR)

AF:

0.767

AC:

34149

AN:

44532

Ashkenazi Jewish (ASJ)

AF:

0.807

AC:

21023

AN:

26040

East Asian (EAS)

AF:

0.598

AC:

23695

AN:

39632

South Asian (SAS)

AF:

0.568

AC:

48858

AN:

85970

European-Finnish (FIN)

AF:

0.757

AC:

40123

AN:

53010

Middle Eastern (MID)

AF:

0.746

AC:

4295

AN:

5754

European-Non Finnish (NFE)

AF:

0.742

AC:

824062

AN:

1110230

Other (OTH)

AF:

0.737

AC:

44414

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

14259

28518

42778

57037

71296

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20176

40352

60528

80704

100880

<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:

0.754

AC:

114403

AN:

151814

Hom.:

43442

Cov.:

AF XY:

0.748

AC XY:

55535

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.803

AC:

33200

AN:

41344

American (AMR)

AF:

0.762

AC:

11647

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.800

AC:

2777

AN:

3472

East Asian (EAS)

AF:

0.601

AC:

3079

AN:

5124

South Asian (SAS)

AF:

0.562

AC:

2693

AN:

4794

European-Finnish (FIN)

AF:

0.752

AC:

7940

AN:

10554

Middle Eastern (MID)

AF:

0.769

AC:

226

AN:

294

European-Non Finnish (NFE)

AF:

0.745

AC:

50641

AN:

67930

Other (OTH)

AF:

0.759

AC:

1603

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1429

2859

4288

5718

7147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

848

1696

2544

3392

4240

<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:

0.764

Hom.:

8413

Bravo

AF:

0.758

Asia WGS

AF:

0.592

AC:

2060

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

5826-12A>C in Intron 24 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 24.7% (1665/6752) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854778). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 22, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.9

(source)

DANN

Benign

0.39

PhyloP100

0.45

Mutation Taster

=45/55

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0020

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