17-18153853-A-T

Variant names:

• chr17-18153853-A-T
• rs712270
• NM_016239.4:c.8045A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 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:9
• Conservation: PhyloP100: 6.34
• Publications: 29 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC105371567 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_016239.4
• 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 VariationId is 226790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016239.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	NM_016239.4	MANE Select	c.8045A>T	p.Tyr2682Phe	missense	Exon 43 of 66	NP_057323.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYO15A	ENST00000647165.2	MANE Select	c.8045A>T	p.Tyr2682Phe	missense	Exon 43 of 66	ENSP00000495481.1
	MYO15A	ENST00000646782.1		n.200A>T		non_coding_transcript_exon	Exon 1 of 22
	MYO15A	ENST00000651214.1		n.191A>T		non_coding_transcript_exon	Exon 1 of 21

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

GnomAD2 exomes AF: 0.336 AC: 83706 AN: 248882 AF XY: 0.336

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 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

African (AFR) AF: 0.226 AC: 7579 AN: 33478

American (AMR) AF: 0.287 AC: 12825 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.402 AC: 10499 AN: 26134

East Asian (EAS) AF: 0.0988 AC: 3922 AN: 39698

South Asian (SAS) AF: 0.217 AC: 18701 AN: 86258

European-Finnish (FIN) AF: 0.437 AC: 23113 AN: 52864

Middle Eastern (MID) AF: 0.309 AC: 1784 AN: 5768

European-Non Finnish (NFE) AF: 0.421 AC: 467979 AN: 1111952

Other (OTH) AF: 0.363 AC: 21917 AN: 60384

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

African (AFR) AF: 0.232 AC: 9607 AN: 41440

American (AMR) AF: 0.299 AC: 4570 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 1380 AN: 3468

East Asian (EAS) AF: 0.0828 AC: 428 AN: 5172

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4808

European-Finnish (FIN) AF: 0.423 AC: 4463 AN: 10558

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.418 AC: 28376 AN: 67952

Other (OTH) AF: 0.322 AC: 680 AN: 2110

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.35
Sift	Benign	0.25	T
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.36
ClinPred		0.088	T
GERP RS		5.1
PromoterAI		-0.053	Neutral
Varity_R		0.19
gMVP		0.41
Mutation Taster		=82/18	polymorphism (auto)

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

Other links and lift over

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