rs2955365

chr17-18120583-G-Achr17-18120583-G-Cchr17-18120583-G-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.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. 12/19 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:11
• Conservation: PhyloP100: 0.806

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 195315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120583-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
MYO15A	NM_016239.4	c.1783G>A	p.Ala595Thr	missense_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.1783G>A	p.Ala595Thr	missense_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.1416G>A		non_coding_transcript_exon_variant	1/1

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

GnomAD3 exomes AF: 0.453 AC: 96609 AN: 213070 Hom.: 23637 AF XY: 0.461 AC XY: 54420 AN XY: 118148

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 SAS exome AF: 0.710

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

Gnomad4 AFR exome AF: 0.496

Gnomad4 AMR exome AF: 0.501

Gnomad4 ASJ exome AF: 0.422

Gnomad4 EAS exome AF: 0.655

Gnomad4 SAS exome AF: 0.702

Gnomad4 FIN exome AF: 0.387

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.395

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

Gnomad4 AFR AF: 0.479

Gnomad4 AMR AF: 0.464

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.636

Gnomad4 SAS AF: 0.704

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.399

Alfa AF: 0.335 Hom.: 7955

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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2015	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). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:4

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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	-0.46	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
MutationTaster	Benign	0.88	P
PrimateAI	Uncertain	0.69	T
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

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

Other links and lift over

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