rs201535856

chr17-18152126-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_016239.4(MYO15A):c.7908C>T(p.Ala2636=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,551,306 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (2 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.37

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]

LOC124903944 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 17-18152126-C-T is Benign according to our data. Variant chr17-18152126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 45762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18152126-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.37 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.7908C>T	p.Ala2636=	synonymous_variant	42/66	ENST00000647165.2
LOC124903944	XR_007065652.1	n.74-220G>A		intron_variant, non_coding_transcript_variant
MYO15A	XM_017024715.3	c.7911C>T	p.Ala2637=	synonymous_variant	40/64
MYO15A	XM_017024714.3	c.7848C>T	p.Ala2616=	synonymous_variant	39/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.7908C>T	p.Ala2636=	synonymous_variant	42/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.00119 AC: 181 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00128 AC: 198 AN: 154580 Hom.: 0 AF XY: 0.00136 AC XY: 111 AN XY: 81884

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.000728

Gnomad ASJ exome AF: 0.000352

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00136

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00231

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00204 AC: 2852 AN: 1399070 Hom.: 2 Cov.: 34 AF XY: 0.00200 AC XY: 1377 AN XY: 690050

Gnomad4 AFR exome AF: 0.000443

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00111

Gnomad4 FIN exome AF: 0.0000204

Gnomad4 NFE exome AF: 0.00240

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00119 AC: 181 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74436

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00137 Hom.: 0

Bravo AF: 0.00121

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	MYO15A: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 16, 2016

p.Ala2636Ala in Exon 42 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% (19/8196) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs201535856). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.87
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201535856; hg19: chr17-18055440;