rs139347804

Positions:

chr17-18142824-G-A

Variant summary

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

The NM_016239.4(MYO15A):c.5894G>A(p.Arg1965His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00567 in 1,612,588 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 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 0.0043 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 33 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.32

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008371383).

BP6

Variant 17-18142824-G-A is Benign according to our data. Variant chr17-18142824-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178445.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=3}. Variant chr17-18142824-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.5894G>A	p.Arg1965His	missense_variant	25/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.5894G>A	p.Arg1965His	missense_variant	25/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

658

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00762

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00725

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00441

AC:

1077

AN:

244424

Hom.:

AF XY:

0.00424

AC XY:

563

AN XY:

132912

show subpopulations

Gnomad AFR exome

AF:

0.00114

Gnomad AMR exome

AF:

0.00123

Gnomad ASJ exome

AF:

0.00192

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.000498

Gnomad FIN exome

AF:

0.00871

Gnomad NFE exome

AF:

0.00694

Gnomad OTH exome

AF:

0.00562

GnomAD4 exome

AF:

0.00582

AC:

8493

AN:

1460306

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4177

AN XY:

726330

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00127

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000803

Gnomad4 FIN exome

AF:

0.00866

Gnomad4 NFE exome

AF:

0.00678

Gnomad4 OTH exome

AF:

0.00482

GnomAD4 genome

AF:

0.00432

AC:

658

AN:

152282

Hom.:

Cov.:

AF XY:

0.00434

AC XY:

323

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.00131

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00762

Gnomad4 NFE

AF:

0.00725

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00576

Hom.:

Bravo

AF:

0.00358

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00100

AC:

ESP6500EA

AF:

0.00756

AC:

ExAC

AF:

0.00430

AC:

520

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00573

EpiControl

AF:

0.00536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MYO15A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Arg1965His in Exon 25 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.6% (43/6736) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs139347804). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;D;D

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.73

T;.;T

MetaRNN

Benign

0.0084

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.74

.;N;N

PrimateAI

Benign

0.20

PROVEAN

Uncertain

-3.1

.;D;.

REVEL

Benign

0.26

Sift

Benign

0.15

.;T;.

Sift4G

Benign

0.42

T;T;.

Polyphen

0.010

.;B;B

Vest4

0.30

MVP

0.60

ClinPred

0.032

GERP RS

0.56

Varity_R

0.059

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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