rs2072653

Variant names:

• chr17-18141784-G-A
• rs2072653
• NM_016239.4:c.5649+14G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-18141784-G-A
• chr17-18141784-G-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.5649+14G>A 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 1,612,992 control chromosomes in the GnomAD database, including 21,468 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2475 hom., cov: 33)
  • Exomes 𝑓: 0.14 (18993 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.909
• Publications: 11 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=-0.76).
• BP6: Variant 17-18141784-G-A is Benign according to our data. Variant chr17-18141784-G-A is described in ClinVar as Benign. ClinVar VariationId is 45750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5649+14G>A		intron_variant	Intron 23 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5649+14G>A		intron_variant	Intron 23 of 65		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000412324.1	n.660+14G>A		intron_variant	Intron 6 of 6	5

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24107 AN: 152060 Hom.: 2468 Cov.: 33

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.261

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.180

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.186 AC: 46397 AN: 249124 AF XY: 0.175

Gnomad AFR exome AF: 0.150

Gnomad AMR exome AF: 0.358

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.503

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.141 AC: 206290 AN: 1460814 Hom.: 18993 Cov.: 32 AF XY: 0.140 AC XY: 102074 AN XY: 726754

African (AFR) AF: 0.144 AC: 4820 AN: 33462

American (AMR) AF: 0.344 AC: 15396 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 2999 AN: 26132

East Asian (EAS) AF: 0.492 AC: 19520 AN: 39682

South Asian (SAS) AF: 0.153 AC: 13152 AN: 86210

European-Finnish (FIN) AF: 0.173 AC: 9202 AN: 53210

Middle Eastern (MID) AF: 0.0853 AC: 492 AN: 5768

European-Non Finnish (NFE) AF: 0.118 AC: 131205 AN: 1111266

Other (OTH) AF: 0.157 AC: 9504 AN: 60366

GnomAD4 genome AF: 0.159 AC: 24124 AN: 152178 Hom.: 2475 Cov.: 33 AF XY: 0.167 AC XY: 12430 AN XY: 74388

African (AFR) AF: 0.148 AC: 6130 AN: 41520

American (AMR) AF: 0.263 AC: 4017 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.503 AC: 2597 AN: 5166

South Asian (SAS) AF: 0.161 AC: 773 AN: 4810

European-Finnish (FIN) AF: 0.180 AC: 1903 AN: 10588

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

European-Non Finnish (NFE) AF: 0.116 AC: 7886 AN: 68014

Other (OTH) AF: 0.158 AC: 333 AN: 2114

Alfa AF: 0.125 Hom.: 2058

Bravo AF: 0.167

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

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

5649+14G>A in Intron 23 of MYO15A: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus se quence and has been identified in 13.8% (479/3462) of African American chromosom es from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS; dbSNP rs2072653). -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Jan 12, 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	-0.76
CADD	Benign	7.0
DANN	Benign	0.82
PhyloP100		-0.91
Mutation Taster		=98/2	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: rs2072653; hg19: chr17-18045098; COSMIC: COSV52753852; COSMIC: COSV52753852;