rs186426892

Variant names:

• chr17-18136626-G-A
• rs186426892
• NM_016239.4:c.4719G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-18136626-G-A
• chr17-18136626-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.4719G>A​(p.Ala1573Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,642 control chromosomes in the GnomAD database, including 11 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 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (10 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.892

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-18136626-G-A is Benign according to our data. Variant chr17-18136626-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178441.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr17-18136626-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00186 (2721/1461320) while in subpopulation MID AF= 0.00693 (40/5768). AF 95% confidence interval is 0.00524. There are 10 homozygotes in gnomad4_exome. There are 1397 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4719G>A	p.Ala1573Ala	synonymous_variant	Exon 15 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4719G>A	p.Ala1573Ala	synonymous_variant	Exon 15 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 209 AN: 152204 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00146 AC: 362 AN: 248576 Hom.: 1 AF XY: 0.00156 AC XY: 211 AN XY: 134974

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.000994

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0000948

Gnomad NFE exome AF: 0.00214

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00186 AC: 2721 AN: 1461320 Hom.: 10 Cov.: 32 AF XY: 0.00192 AC XY: 1397 AN XY: 726966

Gnomad4 AFR exome AF: 0.000807

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.0000756

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00260

GnomAD4 genome AF: 0.00138 AC: 210 AN: 152322 Hom.: 1 Cov.: 33 AF XY: 0.00122 AC XY: 91 AN XY: 74478

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00131 Hom.: 0

Bravo AF: 0.00173

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

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

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO15A: BP4, BP7 -

Jul 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 24, 2020

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ala1573Ala in exon 15 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wi thin the splice consensus sequence, and has been identified in 0.2% (134/64560) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs186426892). -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.073
DANN	Benign	0.50

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: rs186426892; hg19: chr17-18039940; COSMIC: COSV99231381; COSMIC: COSV99231381;