rs854800

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016239.4(MYO15A):c.10431T>C(p.Tyr3477=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 1,613,820 control chromosomes in the GnomAD database, including 450,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 46714 hom., cov: 34)

Exomes 𝑓: 0.74 ( 404091 hom. )

Consequence

MYO15A
NM_016239.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.791

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 17-18173861-T-C is Benign according to our data. Variant chr17-18173861-T-C is described in ClinVar as [Benign]. Clinvar id is 45744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18173861-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.867 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MYO15A	NM_016239.4 linkuse as main transcript	c.10431T>C	p.Tyr3477=	synonymous_variant	65/66	ENST00000647165.2
MYO15A	XM_017024715.3 linkuse as main transcript	c.10434T>C	p.Tyr3478=	synonymous_variant	63/64
MYO15A	XM_017024714.3 linkuse as main transcript	c.10371T>C	p.Tyr3457=	synonymous_variant	62/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.10431T>C	p.Tyr3477=	synonymous_variant	65/66		NM_016239.4	P1	Q9UKN7-1
	ENST00000577847.1 linkuse as main transcript	n.393-1116A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.779

AC:

118554

AN:

152146

Hom.:

46649

Cov.:

show subpopulations

Gnomad AFR

AF:

0.874

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.775

Gnomad ASJ

AF:

0.802

Gnomad EAS

AF:

0.641

Gnomad SAS

AF:

0.586

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.753

Gnomad OTH

AF:

0.773

GnomAD3 exomes

AF:

0.734

AC:

181585

AN:

247468

Hom.:

67559

AF XY:

0.724

AC XY:

97479

AN XY:

134716

show subpopulations

Gnomad AFR exome

AF:

0.871

Gnomad AMR exome

AF:

0.784

Gnomad ASJ exome

AF:

0.809

Gnomad EAS exome

AF:

0.639

Gnomad SAS exome

AF:

0.581

Gnomad FIN exome

AF:

0.749

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.753

GnomAD4 exome

AF:

0.742

AC:

1083874

AN:

1461556

Hom.:

404091

Cov.:

AF XY:

0.736

AC XY:

535235

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.878

Gnomad4 AMR exome

AF:

0.783

Gnomad4 ASJ exome

AF:

0.808

Gnomad4 EAS exome

AF:

0.643

Gnomad4 SAS exome

AF:

0.589

Gnomad4 FIN exome

AF:

0.752

Gnomad4 NFE exome

AF:

0.748

Gnomad4 OTH exome

AF:

0.751

GnomAD4 genome

AF:

0.779

AC:

118680

AN:

152264

Hom.:

46714

Cov.:

AF XY:

0.775

AC XY:

57671

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.874

Gnomad4 AMR

AF:

0.775

Gnomad4 ASJ

AF:

0.802

Gnomad4 EAS

AF:

0.641

Gnomad4 SAS

AF:

0.586

Gnomad4 FIN

AF:

0.747

Gnomad4 NFE

AF:

0.753

Gnomad4 OTH

AF:

0.772

Alfa

AF:

0.755

Hom.:

52895

Bravo

AF:

0.787

Asia WGS

AF:

0.607

AC:

2113

AN:

3478

EpiCase

AF:

0.733

EpiControl

AF:

0.734

ClinVar

Significance: Benign

Submissions summary: Benign:9

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Tyr3477Tyr in Exon 65 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 24.0% (1601/6668) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs854800). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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. -

Autosomal recessive nonsyndromic hearing loss 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -

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

-0.63

Cadd

Benign

0.10

Dann

Benign

0.52

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