rs2280777

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016239.4(MYO15A):c.4954C>T(p.Leu1652=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,613,386 control chromosomes in the GnomAD database, including 233,604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.52 ( 20763 hom., cov: 32)

Exomes 𝑓: 0.54 ( 212841 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.24

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 17-18138193-C-T is Benign according to our data. Variant chr17-18138193-C-T is described in ClinVar as [Benign]. Clinvar id is 226788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18138193-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.24 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.4954C>T	p.Leu1652=	synonymous_variant	17/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.4954C>T	p.Leu1652=	synonymous_variant	17/66		NM_016239.4	P1	Q9UKN7-1
MYO15A	ENST00000646238.1 linkuse as main transcript	n.218C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes

AF:

0.517

AC:

78615

AN:

151956

Hom.:

20734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.447

Gnomad AMI

AF:

0.511

Gnomad AMR

AF:

0.575

Gnomad ASJ

AF:

0.540

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.388

Gnomad FIN

AF:

0.604

Gnomad MID

AF:

0.449

Gnomad NFE

AF:

0.537

Gnomad OTH

AF:

0.510

GnomAD3 exomes

AF:

0.532

AC:

132499

AN:

249148

Hom.:

36364

AF XY:

0.519

AC XY:

70165

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.440

Gnomad AMR exome

AF:

0.652

Gnomad ASJ exome

AF:

0.550

Gnomad EAS exome

AF:

0.595

Gnomad SAS exome

AF:

0.377

Gnomad FIN exome

AF:

0.608

Gnomad NFE exome

AF:

0.524

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.536

AC:

783490

AN:

1461312

Hom.:

212841

Cov.:

AF XY:

0.530

AC XY:

385428

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.440

Gnomad4 AMR exome

AF:

0.641

Gnomad4 ASJ exome

AF:

0.545

Gnomad4 EAS exome

AF:

0.593

Gnomad4 SAS exome

AF:

0.379

Gnomad4 FIN exome

AF:

0.611

Gnomad4 NFE exome

AF:

0.542

Gnomad4 OTH exome

AF:

0.535

GnomAD4 genome

AF:

0.517

AC:

78676

AN:

152074

Hom.:

20763

Cov.:

AF XY:

0.519

AC XY:

38609

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.446

Gnomad4 AMR

AF:

0.576

Gnomad4 ASJ

AF:

0.540

Gnomad4 EAS

AF:

0.593

Gnomad4 SAS

AF:

0.386

Gnomad4 FIN

AF:

0.604

Gnomad4 NFE

AF:

0.537

Gnomad4 OTH

AF:

0.513

Alfa

AF:

0.530

Hom.:

42759

Bravo

AF:

0.514

Asia WGS

AF:

0.487

AC:

1696

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Leu1652Leu in Exon 17 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 47.4% (3316/6998) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2280777). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 3

Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

Cadd

Benign

8.8

Dann

Benign

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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