rs117612144

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016239.4(MYO15A):c.3026C>A(p.Pro1009His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00333 in 1,612,882 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 67 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 0.0910

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006921023).

BP6

Variant 17-18121826-C-A is Benign according to our data. Variant chr17-18121826-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 226782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18121826-C-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00373 (568/152306) while in subpopulation EAS AF= 0.0342 (177/5174). AF 95% confidence interval is 0.0301. There are 2 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.3026C>A	p.Pro1009His	missense_variant	2/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.3026C>A	p.Pro1009His	missense_variant	2/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1
MYO15A	ENST00000583079.1 linkuse as main transcript	n.2659C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

567

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0339

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0216

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00206

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00591

AC:

1466

AN:

247930

Hom.:

AF XY:

0.00568

AC XY:

767

AN XY:

135008

show subpopulations

Gnomad AFR exome

AF:

0.000131

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000200

Gnomad EAS exome

AF:

0.0409

Gnomad SAS exome

AF:

0.000425

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.00234

Gnomad OTH exome

AF:

0.00365

GnomAD4 exome

AF:

0.00329

AC:

4807

AN:

1460576

Hom.:

Cov.:

AF XY:

0.00327

AC XY:

2374

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.000115

Gnomad4 EAS exome

AF:

0.0470

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.0189

Gnomad4 NFE exome

AF:

0.00155

Gnomad4 OTH exome

AF:

0.00268

GnomAD4 genome

AF:

0.00373

AC:

568

AN:

152306

Hom.:

Cov.:

AF XY:

0.00459

AC XY:

342

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0342

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0216

Gnomad4 NFE

AF:

0.00206

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00342

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00613

AC:

740

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00279

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 30, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYO15A: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, flagged submission	clinical testing	Molecular Diagnosis Center for Deafness	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 12, 2015

p.Pro1009His in exon 2 of MYO15A: This variant was reported as homozygous in one Chinese (Hans) individual with hearing loss (Yang 2013); however, it is not e xpected to have clinical significance because it has been identified in 4.6% (39 5/8578) of East Asian chromosomes, including 14 homozygous individuals, by the E xome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11761 2144). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.29

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.036

T;T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.52

T;.;T

MetaRNN

Benign

0.0069

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

2.0

.;M;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

.;N;.

REVEL

Pathogenic

0.73

Sift

Uncertain

0.010

.;D;.

Sift4G

Uncertain

0.0050

D;D;.

Polyphen

0.97

.;D;D

Vest4

0.48

MVP

0.68

ClinPred

0.043

GERP RS

0.42

Varity_R

0.14

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over