17-18140503-C-T

Variant names:

• chr17-18140503-C-T
• rs2072652
• NM_016239.4:c.5212-14C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.5212-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,274 control chromosomes in the GnomAD database, including 21,549 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2492 hom., cov: 33)
  • Exomes 𝑓: 0.14 (19057 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.76
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-18140503-C-T is Benign according to our data. Variant chr17-18140503-C-T is described in ClinVar as Benign. ClinVar VariationId is 45748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5212-14C>T		intron_variant	Intron 19 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5212-14C>T		intron_variant	Intron 19 of 65		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000412324.1	n.209C>T		non_coding_transcript_exon_variant	Exon 3 of 7	5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24150 AN: 152128 Hom.: 2487 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.506

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.187 AC: 46386 AN: 248106 AF XY: 0.175

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.360

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.506

Gnomad FIN exome AF: 0.170

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 206422 AN: 1461028 Hom.: 19057 Cov.: 53 AF XY: 0.140 AC XY: 102114 AN XY: 726822

African (AFR) AF: 0.144 AC: 4808 AN: 33478

American (AMR) AF: 0.346 AC: 15467 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3001 AN: 26136

East Asian (EAS) AF: 0.493 AC: 19589 AN: 39700

South Asian (SAS) AF: 0.152 AC: 13153 AN: 86254

European-Finnish (FIN) AF: 0.173 AC: 9098 AN: 52614

Middle Eastern (MID) AF: 0.0850 AC: 490 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131297 AN: 1111972

Other (OTH) AF: 0.158 AC: 9519 AN: 60384

GnomAD4 genome AF: 0.159 AC: 24162 AN: 152246 Hom.: 2492 Cov.: 33 AF XY: 0.167 AC XY: 12469 AN XY: 74460

African (AFR) AF: 0.147 AC: 6122 AN: 41536

American (AMR) AF: 0.264 AC: 4034 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3472

East Asian (EAS) AF: 0.506 AC: 2607 AN: 5156

South Asian (SAS) AF: 0.161 AC: 776 AN: 4830

European-Finnish (FIN) AF: 0.181 AC: 1917 AN: 10618

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7889 AN: 68012

Other (OTH) AF: 0.157 AC: 332 AN: 2116

Alfa AF: 0.111 Hom.: 529

Bravo AF: 0.167

Asia WGS AF: 0.298 AC: 1037 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

5212-14C>T in Intron 19 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 14.0% (462/3304) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2072652). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: 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 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	-0.91
CADD	Benign	1.3
DANN	Benign	0.37
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2072652; hg19: chr17-18043817; COSMIC: COSV52752564; COSMIC: COSV52752564;