rs184435771

Positions:

chr17-18154714-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_016239.4(MYO15A):c.8183G>A(p.Arg2728His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 9.23

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:

LOC105371567 (HGNC:):

LOC105371567 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-18154714-G-A is Pathogenic according to our data. Variant chr17-18154714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228276.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18154714-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-18154714-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.8183G>A	p.Arg2728His	missense_variant	45/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.8183G>A	p.Arg2728His	missense_variant	45/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000189

AC:

AN:

249056

Hom.:

AF XY:

0.000178

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000704

Gnomad NFE exome

AF:

0.000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000890

AC:

130

AN:

1461450

Hom.:

Cov.:

AF XY:

0.0000867

AC XY:

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000679

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000112

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000106

Hom.:

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000244

AC:

ESP6500EA

AF:

0.000238

AC:

ExAC

AF:

0.000223

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 31, 2017	A heterozygous missense variant was identified, NM_016239.3(MYO15A):c.8183G>A in exon 45 of the MYO15A gene. This substitution is predicted to create a minor amino acid change from an arginine to a histidine at position 2728, NP_057323.3(MYO15A):p.(Arg2728His).The amino acidat this position has high conservation (100 vertebrates, UCSC). In silico software predicts this variant to be disease causing (Polyphen, SIFT, CADD, Mutation Taster). It is not situated in a known functional domain. The variant is present in the gnomAD database at a frequency of 0.019% (53 in 276732, 0 homozygotes). It has been previously reported as likely pathogenic in patients with hearing loss in compound heterozygous state (Brownstein Z, et al. (2011), Yang, T. et al. (2013), ClinVar).Parental testing has indicated the MYO15A variants are compoundheterozygous.Based on current information, this variant has been classified as LIKELY PATHOGENIC.NB: This variant has been reclassified as likely pathogenic due to being in trans with the c.1137delC variant, confirming compound heterozygous inheritance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 29, 2017	The MYO15A c.8183G>A (p.Arg2728His) missense variant has been reported in two studies in which it was identified in a compound heterozygous state with a frameshift variant in three individuals with nonsyndromic hearing loss (Brownstein et al. 2011; Yang et al. 2013). One of these individuals was Han Chinese with no family history of hearing loss, and the other two individuals were siblings of Ashkenazi Jewish heritage. The variant co-segregated with the recessively inherited hearing loss observed in the family, as the father and a third sibling were heterozygous for the p.Arg2728His variant and unaffected, and the mother was heterozygous for the frameshift and unaffected. The p.Arg2728His variant was also identified in 3/288 ethnically matched unrelated deaf alleles but was absent from 716 ethnically matched control alleles. It is reported at a frequency of 0.001059 in the European (Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg2728His variant is classified as likely pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	research	Laboratory of Prof. Karen Avraham, Tel Aviv University	Oct 27, 2020	Recessive, congenital SNHL -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2728 of the MYO15A protein (p.Arg2728His). This variant is present in population databases (rs184435771, gnomAD 0.06%). This missense change has been observed in individuals with deafness (PMID: 21917145, 30622556, 31827275, 32747562, 33398081). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 228276). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MYO15A protein function. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Nov 14, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21917145, 27375115, 25792667, 30579064, 23767834, 30622556, 34426522, 37108562, 31827275, 32747562, 33398081, 35982127) -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2017

- -

Hearing impairment

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PS1_Strong, PM2_Moderate, PM3_Moderate, PP1_Supporting, PP3_Supporting -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 03, 2020

The p.Arg2728His variant in MYO15A has been previously reported in 5 probands with hearing loss, 4 of whom were compound heterozygous for a pathogenic or likely pathogenic variant in MYO15A (Brownstein 2011, Yang 2013, LMM Data). In one family, the p.Arg2728His variant and a frameshift variant were confirmed in trans in the proband, segregated with hearing loss in one affected family member, and two unaffected siblings were either either a carrier or wild-type (Brownstein 2011). This variant has been identified in 0.07% (17/24776) of Finnish chromosomes (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hearing loss. ACMG/AMP criteria applied: PM3_Strong, PP1, PM2_Supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;D;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.;D

M_CAP

Pathogenic

0.38

MetaRNN

Uncertain

0.60

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.5

.;M;M

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.7

.;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0080

.;D;.

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

.;D;D

Vest4

0.68

MVP

0.93

ClinPred

0.87

GERP RS

5.3

Varity_R

0.37

gMVP

0.69

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