17-18130805-A-T

Position:

chr17-18130805-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_016239.4(MYO15A):c.4033A>T(p.Ile1345Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00313 in 1,605,052 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0033 ( 12 hom. )

Consequence

MYO15A
NM_016239.4 missense, splice_region

Scores

Splicing: ADA: 0.01628

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 2.39

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01732254).

BP6

Variant 17-18130805-A-T is Benign according to our data. Variant chr17-18130805-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198880.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=2, Likely_benign=2}. Variant chr17-18130805-A-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.4033A>T	p.Ile1345Leu	missense_variant, splice_region_variant	8/66	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.4033A>T	p.Ile1345Leu	missense_variant, splice_region_variant	8/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00182

AC:

264

AN:

145434

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000655

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000512

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00341

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00153

AC:

377

AN:

246486

Hom.:

AF XY:

0.00159

AC XY:

213

AN XY:

133988

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000378

Gnomad NFE exome

AF:

0.00311

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.00326

AC:

4761

AN:

1459506

Hom.:

Cov.:

AF XY:

0.00313

AC XY:

2275

AN XY:

726164

show subpopulations

Gnomad4 AFR exome

AF:

0.000540

Gnomad4 AMR exome

AF:

0.000314

Gnomad4 ASJ exome

AF:

0.000230

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000604

Gnomad4 NFE exome

AF:

0.00413

Gnomad4 OTH exome

AF:

0.00169

GnomAD4 genome

AF:

0.00181

AC:

264

AN:

145546

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

121

AN XY:

70726

show subpopulations

Gnomad4 AFR

AF:

0.000653

Gnomad4 AMR

AF:

0.000412

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000512

Gnomad4 NFE

AF:

0.00341

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00191

Hom.:

Bravo

AF:

0.00174

ESP6500AA

AF:

0.000487

AC:

ESP6500EA

AF:

0.00406

AC:

ExAC

AF:

0.00150

AC:

182

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 12, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	MYO15A: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 21, 2019	- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Ile1345Leu in Exon 08 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (27/6778) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS). -

MYO15A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 21, 2022

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

0.12

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.28

.;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

0.36

MutationAssessor

Benign

1.2

L;L

MutationTaster

Benign

1.0

PROVEAN

Benign

-0.71

N;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.019

D;.

Sift4G

Uncertain

0.0090

D;.

Vest4

0.46

MutPred

0.41

Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);

MVP

0.84

ClinPred

0.023

GERP RS

2.7

Varity_R

0.19

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.016

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.20

Position offset: 0

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