rs712270

Positions:

• chr17-18153853-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.8045A>T​(p.Tyr2682Phe) variant causes a missense change. The variant allele was found at a frequency of 0.384 in 1,613,226 control chromosomes in the GnomAD database, including 124,975 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9358 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115617 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.34

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]

LOC105371567 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023952425).
• BP6: Variant 17-18153853-A-T is Benign according to our data. Variant chr17-18153853-A-T is described in ClinVar as [Benign]. Clinvar id is 226790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18153853-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.8045A>T	p.Tyr2682Phe	missense_variant	43/66	ENST00000647165.2
LOC105371567	XR_001752809.1	n.329T>A		non_coding_transcript_exon_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.8045A>T	p.Tyr2682Phe	missense_variant	43/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51019 AN: 151856 Hom.: 9356 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.428

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.398

Gnomad EAS AF: 0.0822

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.423

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.418

Gnomad OTH AF: 0.326

GnomAD3 exomes AF: 0.336 AC: 83706 AN: 248882 Hom.: 15506 AF XY: 0.336 AC XY: 45427 AN XY: 135276

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.410

Gnomad EAS exome AF: 0.0885

Gnomad SAS exome AF: 0.217

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.412

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.389 AC: 568319 AN: 1461252 Hom.: 115617 Cov.: 53 AF XY: 0.384 AC XY: 278872 AN XY: 726932

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.287

Gnomad4 ASJ exome AF: 0.402

Gnomad4 EAS exome AF: 0.0988

Gnomad4 SAS exome AF: 0.217

Gnomad4 FIN exome AF: 0.437

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.336 AC: 51031 AN: 151974 Hom.: 9358 Cov.: 32 AF XY: 0.330 AC XY: 24513 AN XY: 74320

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.299

Gnomad4 ASJ AF: 0.398

Gnomad4 EAS AF: 0.0828

Gnomad4 SAS AF: 0.215

Gnomad4 FIN AF: 0.423

Gnomad4 NFE AF: 0.418

Gnomad4 OTH AF: 0.322

Alfa AF: 0.396 Hom.: 9511

Bravo AF: 0.320

TwinsUK AF: 0.419 AC: 1555

ALSPAC AF: 0.435 AC: 1675

ESP6500AA AF: 0.227 AC: 861

ESP6500EA AF: 0.407 AC: 3348

ExAC AF: 0.334 AC: 40310

Asia WGS AF: 0.161 AC: 562 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Tyr2682Phe in Exon 43 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 39.8% (2646/6644) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs712270). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Benign	0.019	T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;.;T
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.000024	P;P
PrimateAI	Uncertain	0.54	T
Sift4G	Benign	0.11	T;T;.
Polyphen		1.0	.;D;D
Vest4		0.36
ClinPred		0.088	T
GERP RS		5.1
Varity_R		0.19
gMVP		0.41

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

Other links and lift over

dbSNP: rs712270; hg19: chr17-18057167; COSMIC: COSV52761528; COSMIC: COSV52761528;