rs182293382

Variant names:

• chr17-18121362-C-T
• rs182293382
• NM_016239.4:c.2562C>T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016239.4(MYO15A):​c.2562C>T​(p.Cys854Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,483,108 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (36 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.838

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-18121362-C-T is Benign according to our data. Variant chr17-18121362-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.838 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00393 (597/151732) while in subpopulation NFE AF= 0.00428 (290/67802). AF 95% confidence interval is 0.00387. There are 3 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.2562C>T	p.Cys854Cys	synonymous_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.2562C>T	p.Cys854Cys	synonymous_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.2195C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 597 AN: 151624 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00428

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00404 AC: 363 AN: 89774 Hom.: 4 AF XY: 0.00391 AC XY: 197 AN XY: 50322

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00166

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000308

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00538

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00551 AC: 7332 AN: 1331376 Hom.: 36 Cov.: 37 AF XY: 0.00531 AC XY: 3475 AN XY: 654970

Gnomad4 AFR exome AF: 0.000665

Gnomad4 AMR exome AF: 0.00337

Gnomad4 ASJ exome AF: 0.00166

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000370

Gnomad4 FIN exome AF: 0.0164

Gnomad4 NFE exome AF: 0.00597

Gnomad4 OTH exome AF: 0.00481

GnomAD4 genome AF: 0.00393 AC: 597 AN: 151732 Hom.: 3 Cov.: 32 AF XY: 0.00444 AC XY: 329 AN XY: 74142

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00387

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.00428

Gnomad4 OTH AF: 0.00523

Alfa AF: 0.00447 Hom.: 1

Bravo AF: 0.00287

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO15A: BP4, BP7, BS2 -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1 Benign:1

Sep 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

May 22, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Cys854Cys in exon 2 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 0.7% (4/552) of Eur opean chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadin stitute.org; dbSNP rs182293382). -

MYO15A-related disorder Benign:1

Feb 27, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.1
DANN	Benign	0.75

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: rs182293382; hg19: chr17-18024676;