17-18120187-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_016239.4(MYO15A):c.1387A>G(p.Met463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,908 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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 0.0011 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.94

Publications

10 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011315584).

BP6

Variant 17-18120187-A-G is Benign according to our data. Variant chr17-18120187-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 227634.

BS2

High Homozygotes in GnomAd4 at 2 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.1387A>G	p.Met463Val	missense	Exon 2 of 66	NP_057323.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.1387A>G	p.Met463Val	missense	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.1020A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.00104

AC:

159

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00289

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00173

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00127

AC:

315

AN:

248164

AF XY:

0.00144

show subpopulations

Gnomad AFR exome

AF:

0.000130

Gnomad AMR exome

AF:

0.000638

Gnomad ASJ exome

AF:

0.00290

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.00154

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00142

AC:

2076

AN:

1460570

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1086

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000514

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00225

AC:

194

AN:

86258

European-Finnish (FIN)

AF:

0.000153

AC:

AN:

52154

Middle Eastern (MID)

AF:

0.00225

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00152

AC:

1695

AN:

1111978

Other (OTH)

AF:

0.00111

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00105

AC:

160

AN:

152338

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.000192

AC:

AN:

41584

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00290

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00173

AC:

118

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00138

Hom.:

Bravo

AF:

0.000963

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00154

AC:

ExAC

AF:

0.00125

AC:

151

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00184

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 3 (1)

MYO15A-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.015

Eigen

Benign

-0.15

Eigen_PC

Benign

0.057

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.65

M_CAP

Benign

0.0061

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

2.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.3

REVEL

Benign

0.086

Sift

Benign

0.096

Sift4G

Benign

0.091

Polyphen

0.070

Vest4

0.37

MVP

0.33

ClinPred

0.0075

GERP RS

5.4

Varity_R

0.17

gMVP

0.64

Mutation Taster

=98/2

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