rs76468019

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.3413A>G(p.Gln1138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,613,148 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene MYO15A is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.019 ( 71 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 229 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.510

Publications

12 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018774569).

BP6

Variant 17-18122213-A-G is Benign according to our data. Variant chr17-18122213-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

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.3413A>G	p.Gln1138Arg	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.3413A>G	p.Gln1138Arg	missense	Exon 2 of 66	ENSP00000495481.1	Q9UKN7-1
	MYO15A	ENST00000583079.1	TSL:6	n.3046A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2910

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.107

Gnomad SAS

AF:

0.00868

Gnomad FIN

AF:

0.00837

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.0143

GnomAD2 exomes

AF:

0.0139

AC:

3447

AN:

248824

AF XY:

0.0125

show subpopulations

Gnomad AFR exome

AF:

0.0481

Gnomad AMR exome

AF:

0.00333

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.00779

Gnomad NFE exome

AF:

0.00136

Gnomad OTH exome

AF:

0.00778

GnomAD4 exome

AF:

0.00523

AC:

7633

AN:

1460848

Hom.:

229

Cov.:

AF XY:

0.00508

AC XY:

3690

AN XY:

726714

show subpopulations

African (AFR)

AF:

0.0498

AC:

1667

AN:

33480

American (AMR)

AF:

0.00367

AC:

164

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00233

AC:

AN:

26136

East Asian (EAS)

AF:

0.0858

AC:

3407

AN:

39700

South Asian (SAS)

AF:

0.00546

AC:

471

AN:

86258

European-Finnish (FIN)

AF:

0.00811

AC:

425

AN:

52408

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000665

AC:

740

AN:

1111994

Other (OTH)

AF:

0.0109

AC:

661

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

560

1119

1679

2238

2798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

130

260

390

520

650

<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:

0.0191

AC:

2910

AN:

152300

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1433

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0484

AC:

2011

AN:

41554

American (AMR)

AF:

0.00673

AC:

103

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3472

East Asian (EAS)

AF:

0.107

AC:

552

AN:

5164

South Asian (SAS)

AF:

0.00869

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00837

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68018

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

140

280

420

560

700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.00778

Hom.:

Bravo

AF:

0.0214

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0425

AC:

173

ESP6500EA

AF:

0.000958

AC:

ExAC

AF:

0.0141

AC:

1703

Asia WGS

AF:

0.0410

AC:

144

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.000948

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Autosomal recessive nonsyndromic hearing loss 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.18

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.0094

Eigen

Benign

-2.6

Eigen_PC

Benign

-2.5

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.17

MetaRNN

Benign

0.0019

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

-0.51

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.020

REVEL

Benign

0.16

Sift

Benign

0.51

Sift4G

Benign

0.89

Polyphen

0.0

Vest4

0.014

ClinPred

0.0097

GERP RS

-3.5

Varity_R

0.029

gMVP

0.12

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over