rs861278

chr17-18156180-C-T

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.8460-15C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,590 control chromosomes in the GnomAD database, including 124,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (9348 hom., cov: 32)
  • Exomes 𝑓: 0.39 (115383 hom.)
• Consequence: MYO15A NM_016239.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.402

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-18156180-C-T is Benign according to our data. Variant chr17-18156180-C-T is described in ClinVar as [Benign]. Clinvar id is 45769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18156180-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.413 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.8460-15C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000647165.2
MYO15A	XM_017024714.3	c.8400-15C>T		splice_polypyrimidine_tract_variant, intron_variant
MYO15A	XM_017024715.3	c.8463-15C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.8460-15C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.336 AC: 51026 AN: 151988 Hom.: 9346 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.0869

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.422

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.417

Gnomad OTH AF: 0.329

GnomAD3 exomes AF: 0.334 AC: 83017 AN: 248462 Hom.: 15278 AF XY: 0.334 AC XY: 45022 AN XY: 134902

Gnomad AFR exome AF: 0.223

Gnomad AMR exome AF: 0.276

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.0908

Gnomad SAS exome AF: 0.215

Gnomad FIN exome AF: 0.437

Gnomad NFE exome AF: 0.411

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.388 AC: 567652 AN: 1461482 Hom.: 115383 Cov.: 50 AF XY: 0.383 AC XY: 278553 AN XY: 727044

Gnomad4 AFR exome AF: 0.227

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.400

Gnomad4 EAS exome AF: 0.101

Gnomad4 SAS exome AF: 0.215

Gnomad4 FIN exome AF: 0.438

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.363

GnomAD4 genome AF: 0.336 AC: 51039 AN: 152108 Hom.: 9348 Cov.: 32 AF XY: 0.330 AC XY: 24508 AN XY: 74364

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.0875

Gnomad4 SAS AF: 0.212

Gnomad4 FIN AF: 0.422

Gnomad4 NFE AF: 0.417

Gnomad4 OTH AF: 0.325

Alfa AF: 0.385 Hom.: 2166

Bravo AF: 0.320

Asia WGS AF: 0.162 AC: 565 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	8460-15C>T in Intron 47 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 40.0% (2731/6830) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs861278). -
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	-	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	3.8
Dann	Benign	0.68

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: rs861278; hg19: chr17-18059494; COSMIC: COSV52754137; COSMIC: COSV52754137;