rs756565842

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016239.4(MYO15A):c.7436A>G(p.Gln2479Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,598,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.02

Publications

0 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:

LOC124903944 (HGNC:):

LOC124903944 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.128171).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4 link	c.7436A>G	p.Gln2479Arg	missense_variant	Exon 38 of 66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 link	c.7439A>G	p.Gln2480Arg	missense_variant	Exon 36 of 64		XP_016880204.1
MYO15A	XM_017024714.3 link	c.7376A>G	p.Gln2459Arg	missense_variant	Exon 35 of 63		XP_016880203.1
LOC124903944	XR_007065652.1 link	n.377+727T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 link	c.7436A>G	p.Gln2479Arg	missense_variant	Exon 38 of 66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000271

AC:

AN:

221358

AF XY:

0.0000500

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000374

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000484

AC:

AN:

1446426

Hom.:

Cov.:

AF XY:

0.00000696

AC XY:

AN XY:

718360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33136

American (AMR)

AF:

0.00

AC:

AN:

42280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25788

East Asian (EAS)

AF:

0.000154

AC:

AN:

38872

South Asian (SAS)

AF:

0.00

AC:

AN:

84274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52230

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5088

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1105012

Other (OTH)

AF:

0.0000167

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000192

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 20, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Gln2479Arg variant in MYO15A has not been previously reported in individua ls with hearing loss, but has been reported in ClinVar (Variation ID# 322160) as of uncertain significant. This variant has been identified in 5/15380 East Asi an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs756565842). Computational prediction tools and conservatio n analyses do not provide strong support for or against an impact to the protein . In summary, the clinical significance of the p.Gln2479Arg variant is uncertain . -

Inborn genetic diseases

Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.7436A>G (p.Q2479R) alteration is located in exon 38 (coding exon 37) of the MYO15A gene. This alteration results from a A to G substitution at nucleotide position 7436, causing the glutamine (Q) at amino acid position 2479 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Uncertain:1

Jan 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2479 of the MYO15A protein (p.Gln2479Arg). This variant is present in population databases (rs756565842, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYO15A-related conditions. ClinVar contains an entry for this variant (Variation ID: 322160). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MYO15A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T;T

Eigen

Benign

-0.11

Eigen_PC

Benign

0.011

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.54

T;.;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Uncertain

-0.14

MutationAssessor

Benign

1.9

.;L;L

PhyloP100

3.0

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.6

.;D;.

REVEL

Uncertain

0.33

Sift

Uncertain

0.0070

.;D;.

Sift4G

Uncertain

0.013

D;D;.

Polyphen

0.014

.;B;B

Vest4

0.30

MutPred

0.22

Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);Gain of MoRF binding (P = 0.0186);

MVP

0.70

ClinPred

0.23

GERP RS

4.0

Varity_R

0.19

gMVP

0.56

Mutation Taster

=63/37

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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rs756565842

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over