rs876657899

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_016239.4(MYO15A):c.4987G>A(p.Asp1663Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.91

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.4987G>A	p.Asp1663Asn	missense_variant	Exon 17 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.4987G>A	p.Asp1663Asn	missense_variant	Exon 17 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000646238.1 link	n.251G>A		non_coding_transcript_exon_variant	Exon 2 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248768

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460864

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111992

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 15, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Asp1663Asn variant in MYO15A has not been previously reported in individua ls with hearing loss and was absent from large population studies. Computational prediction tools and conservation analyses suggest that the Asp1663Asn variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. In summary, the clinical significance of the p.Asp1663Asn v ariant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;D;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;.;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

.;M;M

PhyloP100

9.9

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-5.0

.;D;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0010

.;D;.

Sift4G

Pathogenic

0.0010

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.77

MutPred

0.79

Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);

MVP

0.99

ClinPred

0.92

GERP RS

5.6

Varity_R

0.84

gMVP

0.43

Mutation Taster

=11/89

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over