17-18162574-T-C

Position:

• chr17-18162574-T-C

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.9518-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 1,612,884 control chromosomes in the GnomAD database, including 29,022 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2871 hom., cov: 33)
  • Exomes 𝑓: 0.18 (26151 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Scores: Splicing: ADA: 0.0001856
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.137

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]

MYO15A (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-18162574-T-C is Benign according to our data. Variant chr17-18162574-T-C is described in ClinVar as [Benign]. Clinvar id is 45775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18162574-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.9518-11T>C		intron_variant		ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.9521-11T>C		intron_variant			XP_016880204.1
MYO15A	XM_017024714.3	c.9458-11T>C		intron_variant			XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.9518-11T>C		intron_variant			NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28767 AN: 152100 Hom.: 2857 Cov.: 33

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.146

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.209

GnomAD3 exomes AF: 0.169 AC: 41433 AN: 245520 Hom.: 3916 AF XY: 0.174 AC XY: 23308 AN XY: 133574

Gnomad AFR exome AF: 0.212

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.237

Gnomad EAS exome AF: 0.00452

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.142

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.184 AC: 269281 AN: 1460664 Hom.: 26151 Cov.: 33 AF XY: 0.186 AC XY: 134874 AN XY: 726592

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.243

Gnomad4 EAS exome AF: 0.00280

Gnomad4 SAS exome AF: 0.186

Gnomad4 FIN exome AF: 0.143

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.189 AC: 28830 AN: 152220 Hom.: 2871 Cov.: 33 AF XY: 0.184 AC XY: 13705 AN XY: 74434

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.164

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.00830

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.146

Gnomad4 NFE AF: 0.200

Gnomad4 OTH AF: 0.212

Alfa AF: 0.197 Hom.: 561

Bravo AF: 0.193

Asia WGS AF: 0.108 AC: 374 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	9518-11T>C in Intron 57 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 20.7% (1381/6676) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs62073604). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.10		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: rs62073604; hg19: chr17-18065888;