17-18135761-C-T

Variant names:

• chr17-18135761-C-T
• rs114328138
• NM_016239.4:c.4533C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016239.4(MYO15A):​c.4533C>T​(p.Ala1511Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 1,614,124 control chromosomes in the GnomAD database, including 162 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (57 hom., cov: 33)
  • Exomes 𝑓: 0.0061 (105 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.77

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 17-18135761-C-T is Benign according to our data. Variant chr17-18135761-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.77 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4533C>T	p.Ala1511Ala	synonymous_variant	Exon 13 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4533C>T	p.Ala1511Ala	synonymous_variant	Exon 13 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.0181 AC: 2758 AN: 152160 Hom.: 54 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00838

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00799 AC: 1991 AN: 249164 Hom.: 22 AF XY: 0.00746 AC XY: 1009 AN XY: 135260

Gnomad AFR exome AF: 0.0498

Gnomad AMR exome AF: 0.00345

Gnomad ASJ exome AF: 0.00825

Gnomad EAS exome AF: 0.00189

Gnomad SAS exome AF: 0.00761

Gnomad FIN exome AF: 0.00274

Gnomad NFE exome AF: 0.00553

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.00611 AC: 8935 AN: 1461848 Hom.: 105 Cov.: 31 AF XY: 0.00608 AC XY: 4423 AN XY: 727220

Gnomad4 AFR exome AF: 0.0568

Gnomad4 AMR exome AF: 0.00407

Gnomad4 ASJ exome AF: 0.00838

Gnomad4 EAS exome AF: 0.00139

Gnomad4 SAS exome AF: 0.00795

Gnomad4 FIN exome AF: 0.00238

Gnomad4 NFE exome AF: 0.00448

Gnomad4 OTH exome AF: 0.00977

GnomAD4 genome AF: 0.0183 AC: 2790 AN: 152276 Hom.: 57 Cov.: 33 AF XY: 0.0182 AC XY: 1354 AN XY: 74474

Gnomad4 AFR AF: 0.0509

Gnomad4 AMR AF: 0.00837

Gnomad4 ASJ AF: 0.00950

Gnomad4 EAS AF: 0.00405

Gnomad4 SAS AF: 0.00745

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00565

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0126 Hom.: 16

Bravo AF: 0.0203

Asia WGS AF: 0.0270 AC: 92 AN: 3478

EpiCase AF: 0.00665

EpiControl AF: 0.00622

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala1511Ala in Exon 13 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 4.5% (160/3530) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs114328138). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 05, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.4
DANN	Benign	0.67

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: rs114328138; hg19: chr17-18039075;