rs79230542

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_016239.4(MYO15A):c.10182G>A(p.Ala3394Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00831 in 1,612,076 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0067 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 68 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: -3.91

Publications

4 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)
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

Specifications for MYO15A are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009282678).

BP6

Variant 17-18171737-G-A is Benign according to our data. Variant chr17-18171737-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 45742.

BP7

Synonymous conserved (PhyloP=-3.91 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00672 (1024/152276) while in subpopulation NFE AF = 0.00834 (567/68018). AF 95% confidence interval is 0.00777. There are 5 homozygotes in GnomAd4. There are 486 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.10182G>A	p.Ala3394Ala	synonymous	Exon 63 of 66	NP_057323.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MYO15A	ENST00000647165.2	MANE Select	c.10182G>A	p.Ala3394Ala	synonymous	Exon 63 of 66	ENSP00000495481.1	Q9UKN7-1
MYO15A	ENST00000433411.7	TSL:1	n.1632G>A		non_coding_transcript_exon	Exon 10 of 13
MYO15A	ENST00000578575.1	TSL:1	n.*363G>A		non_coding_transcript_exon	Exon 7 of 9	ENSP00000466630.1	K7EMS7

Frequencies

GnomAD3 genomes

AF:

0.00672

AC:

1023

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00637

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.00622

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00834

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00704

AC:

1728

AN:

245364

AF XY:

0.00706

show subpopulations

Gnomad AFR exome

AF:

0.00772

Gnomad AMR exome

AF:

0.00551

Gnomad ASJ exome

AF:

0.00871

Gnomad EAS exome

AF:

0.00291

Gnomad FIN exome

AF:

0.00309

Gnomad NFE exome

AF:

0.00863

Gnomad OTH exome

AF:

0.00952

GnomAD4 exome

AF:

0.00848

AC:

12375

AN:

1459800

Hom.:

Cov.:

AF XY:

0.00824

AC XY:

5986

AN XY:

726294

show subpopulations

African (AFR)

AF:

0.00750

AC:

251

AN:

33476

American (AMR)

AF:

0.00550

AC:

246

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00792

AC:

207

AN:

26134

East Asian (EAS)

AF:

0.00615

AC:

244

AN:

39700

South Asian (SAS)

AF:

0.00653

AC:

563

AN:

86252

European-Finnish (FIN)

AF:

0.00328

AC:

169

AN:

51448

Middle Eastern (MID)

AF:

0.00938

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00913

AC:

10152

AN:

1111946

Other (OTH)

AF:

0.00810

AC:

489

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

803

1607

2410

3214

4017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

404

808

1212

1616

2020

<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:

0.00672

AC:

1024

AN:

152276

Hom.:

Cov.:

AF XY:

0.00653

AC XY:

486

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00638

AC:

265

AN:

41564

American (AMR)

AF:

0.00510

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00347

AC:

AN:

5182

South Asian (SAS)

AF:

0.00622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00273

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00834

AC:

567

AN:

68018

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00629

Hom.:

Bravo

AF:

0.00729

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00780

AC:

ESP6500EA

AF:

0.00951

AC:

ExAC

AF:

0.00698

AC:

844

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00883

EpiControl

AF:

0.00854

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Autosomal recessive nonsyndromic hearing loss 3 (1)

MYO15A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Uncertain

0.13

CADD

Benign

0.023

(source)

DANN

Uncertain

0.98

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.39

M_CAP

Benign

0.053

MetaRNN

Benign

0.0093

MetaSVM

Uncertain

-0.11

PhyloP100

-3.9

MVP

0.081

ClinPred

0.013

GERP RS

-11

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over