rs2955366

Positions:

• chr17-18120699-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.1899A>G​(p.Pro633=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,543,570 control chromosomes in the GnomAD database, including 113,193 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14513 hom., cov: 31)
  • Exomes 𝑓: 0.36 (98680 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.111

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.09).
• BP6: Variant 17-18120699-A-G is Benign according to our data. Variant chr17-18120699-A-G is described in ClinVar as [Benign]. Clinvar id is 226778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120699-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.111 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.1899A>G	p.Pro633=	synonymous_variant	2/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.1899A>G	p.Pro633=	synonymous_variant	2/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000583079.1	n.1532A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 63952 AN: 150662 Hom.: 14479 Cov.: 31

Gnomad AFR AF: 0.523

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.405

GnomAD3 exomes AF: 0.459 AC: 68279 AN: 148870 Hom.: 16960 AF XY: 0.468 AC XY: 39009 AN XY: 83390

Gnomad AFR exome AF: 0.524

Gnomad AMR exome AF: 0.501

Gnomad ASJ exome AF: 0.420

Gnomad EAS exome AF: 0.628

Gnomad SAS exome AF: 0.708

Gnomad FIN exome AF: 0.396

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.432

GnomAD4 exome AF: 0.358 AC: 499011 AN: 1392804 Hom.: 98680 Cov.: 43 AF XY: 0.369 AC XY: 254271 AN XY: 689474

Gnomad4 AFR exome AF: 0.536

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.421

Gnomad4 EAS exome AF: 0.655

Gnomad4 SAS exome AF: 0.701

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.309

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome AF: 0.425 AC: 64035 AN: 150766 Hom.: 14513 Cov.: 31 AF XY: 0.435 AC XY: 32017 AN XY: 73634

Gnomad4 AFR AF: 0.524

Gnomad4 AMR AF: 0.469

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.637

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.405

Alfa AF: 0.361 Hom.: 3464

Bravo AF: 0.427

Asia WGS AF: 0.647 AC: 2223 AN: 3438

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Pro633Pro in Exon 02 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 42.4% (1017/2398) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2955366). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	1.1
DANN	Benign	0.26

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: rs2955366; hg19: chr17-18024013; COSMIC: COSV52751200;