17-18142183-T-G

Position:

chr17-18142183-T-G

Variant summary

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

The NM_016239.4(MYO15A):c.5754T>G(p.Ile1918Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00219 in 1,613,798 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 1.01

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=0.011315256).

BP6

Variant 17-18142183-T-G is Benign according to our data. Variant chr17-18142183-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178444.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=3}.

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.5754T>G	p.Ile1918Met	missense_variant	24/66	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.5754T>G	p.Ile1918Met	missense_variant	24/66		NM_016239.4	ENSP00000495481	P1	Q9UKN7-1
MYO15A	ENST00000412324.1 linkuse as main transcript			downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

293

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00337

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00192

AC:

478

AN:

249312

Hom.:

AF XY:

0.00190

AC XY:

257

AN XY:

135308

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000981

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00288

Gnomad OTH exome

AF:

0.000990

GnomAD4 exome

AF:

0.00221

AC:

3236

AN:

1461462

Hom.:

Cov.:

AF XY:

0.00229

AC XY:

1663

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00125

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00126

Gnomad4 FIN exome

AF:

0.00315

Gnomad4 NFE exome

AF:

0.00250

Gnomad4 OTH exome

AF:

0.00184

GnomAD4 genome

AF:

0.00192

AC:

293

AN:

152336

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00337

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00271

Hom.:

Bravo

AF:

0.00180

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000458

AC:

ESP6500EA

AF:

0.00268

AC:

ExAC

AF:

0.00195

AC:

237

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign: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 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 26, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 04, 2019

- -

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

Dec 21, 2017

p.Ile1918Met in exon 24 of MYO15A: This variant is not expected to have clinica l significance because it has been identified in 0.3% (394/126610) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs150403702). ACMG/AMP criteria applied: BS1. -

MYO15A-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 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

0.11

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.019

T;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.68

T;.;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

-0.095

MutationAssessor

Benign

0.97

.;L;L

MutationTaster

Benign

0.80

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

.;N;.

REVEL

Uncertain

0.45

Sift

Benign

0.057

.;T;.

Sift4G

Uncertain

0.0060

D;D;.

Polyphen

0.88

.;P;P

Vest4

0.54

MVP

0.77

ClinPred

0.031

GERP RS

1.3

Varity_R

0.088

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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