rs2955365

Variant names:

• chr17-18120583-G-A
• rs2955365
• NM_016239.4:c.1783G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-18120583-G-A
• chr17-18120583-G-C
• chr17-18120583-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.1783G>A​(p.Ala595Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,595,982 control chromosomes in the GnomAD database, including 117,170 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13693 hom., cov: 33)
  • Exomes 𝑓: 0.36 (103477 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.806
• Publications: 42 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0458145E-6).
• BP6: Variant 17-18120583-G-A is Benign according to our data. Variant chr17-18120583-G-A is described in ClinVar as Benign. ClinVar VariationId is 195315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.1783G>A	p.Ala595Thr	missense_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.1783G>A	p.Ala595Thr	missense_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.1416G>A		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62429 AN: 151736 Hom.: 13661 Cov.: 33

Gnomad AFR AF: 0.479

Gnomad AMI AF: 0.417

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.635

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.399

GnomAD2 exomes AF: 0.453 AC: 96609 AN: 213070 AF XY: 0.461

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.634

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.331

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.361 AC: 521016 AN: 1444136 Hom.: 103477 Cov.: 55 AF XY: 0.371 AC XY: 266445 AN XY: 717532

African (AFR) AF: 0.496 AC: 16462 AN: 33204

American (AMR) AF: 0.501 AC: 21658 AN: 43254

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 10900 AN: 25810

East Asian (EAS) AF: 0.655 AC: 25657 AN: 39196

South Asian (SAS) AF: 0.702 AC: 59549 AN: 84838

European-Finnish (FIN) AF: 0.387 AC: 18262 AN: 47222

Middle Eastern (MID) AF: 0.444 AC: 2426 AN: 5470

European-Non Finnish (NFE) AF: 0.310 AC: 342563 AN: 1105478

Other (OTH) AF: 0.395 AC: 23539 AN: 59664

GnomAD4 genome AF: 0.412 AC: 62511 AN: 151846 Hom.: 13693 Cov.: 33 AF XY: 0.422 AC XY: 31300 AN XY: 74216

African (AFR) AF: 0.479 AC: 19844 AN: 41402

American (AMR) AF: 0.464 AC: 7085 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.416 AC: 1442 AN: 3468

East Asian (EAS) AF: 0.636 AC: 3250 AN: 5110

South Asian (SAS) AF: 0.704 AC: 3395 AN: 4820

European-Finnish (FIN) AF: 0.415 AC: 4385 AN: 10578

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.321 AC: 21775 AN: 67880

Other (OTH) AF: 0.399 AC: 841 AN: 2110

Alfa AF: 0.349 Hom.: 13487

Bravo AF: 0.414

TwinsUK AF: 0.304 AC: 1129

ALSPAC AF: 0.300 AC: 1157

ESP6500AA AF: 0.428 AC: 1422

ESP6500EA AF: 0.294 AC: 2198

ExAC AF: 0.427 AC: 49100

Asia WGS AF: 0.651 AC: 2250 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 16, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala595Thr in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 52.9% (41979/79374) of chromosomes across various populations by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org; dbSNP rs2955365). -

Jan 20, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 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. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:4

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.066
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.57	T;.;T
MetaRNN	Benign	0.0000030	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.4	.;L;L
PhyloP100		0.81
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.68	.;N;.
REVEL	Uncertain	0.32
Sift	Uncertain	0.0030	.;D;.
Sift4G	Uncertain	0.011	D;D;.
Polyphen		0.69	.;P;P
Vest4		0.24
ClinPred		0.050	T
GERP RS		3.6
Varity_R		0.097
gMVP		0.25
Mutation Taster		=75/25	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2955365; hg19: chr17-18023897; COSMIC: COSV52751334;