rs144909486

Positions:

chr17-18118854-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_016239.4(MYO15A):c.54G>A(p.Lys18Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,612,666 control chromosomes in the GnomAD database, including 5 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 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 5 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 3.09

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 17-18118854-G-A is Benign according to our data. Variant chr17-18118854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260700.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2, Benign=1}. Variant chr17-18118854-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=3.09 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.54G>A	p.Lys18Lys	synonymous_variant	2/66	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.54G>A	p.Lys18Lys	synonymous_variant	2/66		NM_016239.4	ENSP00000495481.1		Q9UKN7-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00218

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00163

AC:

397

AN:

244140

Hom.:

AF XY:

0.00167

AC XY:

222

AN XY:

133032

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.000702

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00159

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00237

Gnomad OTH exome

AF:

0.00134

GnomAD4 exome

AF:

0.00234

AC:

3414

AN:

1460344

Hom.:

Cov.:

AF XY:

0.00230

AC XY:

1672

AN XY:

726366

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000809

Gnomad4 ASJ exome

AF:

0.00541

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00138

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00265

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00141

AC:

215

AN:

152322

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00218

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00198

Hom.:

Bravo

AF:

0.00151

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MYO15A: BP4, BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2021	Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 24498627) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 25, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2016	p.Lys18Lys in exon 02 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.2% (134/56718) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs144909486). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.54

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