rs183256997

chr17-18136695-G-Achr17-18136695-G-Cchr17-18136695-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016239.4(MYO15A):c.4779+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,593,516 control chromosomes in the GnomAD database, including 13 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 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (12 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.73

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-18136695-G-A is Benign according to our data. Variant chr17-18136695-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45747.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=3}. Variant chr17-18136695-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.4779+9G>A		intron_variant		ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.4779+9G>A		intron_variant			NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152268 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000916

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00373

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00236 AC: 505 AN: 214016 Hom.: 2 AF XY: 0.00228 AC XY: 265 AN XY: 116390

Gnomad AFR exome AF: 0.000690

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.000319

Gnomad EAS exome AF: 0.000190

Gnomad SAS exome AF: 0.00214

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00330 AC: 4751 AN: 1441130 Hom.: 12 Cov.: 32 AF XY: 0.00329 AC XY: 2351 AN XY: 715552

Gnomad4 AFR exome AF: 0.000572

Gnomad4 AMR exome AF: 0.00218

Gnomad4 ASJ exome AF: 0.000271

Gnomad4 EAS exome AF: 0.0000770

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000476

Gnomad4 NFE exome AF: 0.00383

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.00212 AC: 323 AN: 152386 Hom.: 1 Cov.: 33 AF XY: 0.00199 AC XY: 148 AN XY: 74526

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00373

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00135 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MYO15A: BS2 -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 15, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	4779+9G>A in Intron 15 of MYO15A: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence and has been identified in 0.4% (27/6820) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 28, 2016	- -

MYO15A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2019

This variant is classified as likely 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	-0.86
Cadd	Benign	0.14
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs183256997; hg19: chr17-18040009;