17-18173833-G-A

Position:

chr17-18173833-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_016239.4(MYO15A):c.10403G>A(p.Arg3468Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,613,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 5.61

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:

MYO15A (HGNC:):

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0093713105).

BP6

Variant 17-18173833-G-A is Benign according to our data. Variant chr17-18173833-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227631.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.10403G>A	p.Arg3468Gln	missense_variant	65/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1
MYO15A	XM_017024715.3 linkuse as main transcript	c.10406G>A	p.Arg3469Gln	missense_variant	63/64		XP_016880204.1
MYO15A	XM_017024714.3 linkuse as main transcript	c.10343G>A	p.Arg3448Gln	missense_variant	62/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.10403G>A	p.Arg3468Gln	missense_variant	65/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.00193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000601

AC:

149

AN:

248118

Hom.:

AF XY:

0.000682

AC XY:

AN XY:

134940

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00627

Gnomad EAS exome

AF:

0.00201

Gnomad SAS exome

AF:

0.000490

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000134

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000287

AC:

420

AN:

1460976

Hom.:

Cov.:

AF XY:

0.000315

AC XY:

229

AN XY:

726820

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00628

Gnomad4 EAS exome

AF:

0.000857

Gnomad4 SAS exome

AF:

0.000475

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000101

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000361

AC:

AN:

152342

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00518

Gnomad4 EAS

AF:

0.00193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000420

Hom.:

Bravo

AF:

0.000404

ESP6500AA

AF:

0.000255

AC:

ESP6500EA

AF:

0.000362

AC:

ExAC

AF:

0.000546

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 20, 2024

The c.10403G>A (p.R3468Q) alteration is located in exon 65 (coding exon 64) of the MYO15A gene. This alteration results from a G to A substitution at nucleotide position 10403, causing the arginine (R) at amino acid position 3468 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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 specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

p.Arg3468Gln in exon 65 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals (including mouse, rat, and hedgehog) have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, computa tional prediction tools do not suggest a high likelihood of impact to the protei n. It has also been identified in 0.3% (21/8552) of East Asian chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 0456053). -

MYO15A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;T;T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.83

T;.;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0094

T;T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Uncertain

2.5

.;M;M;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.2

.;N;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.15

.;T;.;.

Sift4G

Uncertain

0.049

D;D;.;T

Polyphen

0.60

.;P;P;.

Vest4

0.23

MVP

0.74

ClinPred

0.054

GERP RS

2.6

Varity_R

0.080

gMVP

0.43

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