rs16960961

Variant names:

• chr17-18151139-G-A
• rs16960961
• NM_016239.4:c.7503G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016239.4(MYO15A):​c.7503G>A​(p.Thr2501Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0405 in 1,613,918 control chromosomes in the GnomAD database, including 1,662 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (85 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1577 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.36
• Publications: 7 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

LOC124903944 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-18151139-G-A is Benign according to our data. Variant chr17-18151139-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 45760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0274 (4176/152232) while in subpopulation NFE AF = 0.0438 (2975/67990). AF 95% confidence interval is 0.0424. There are 85 homozygotes in GnomAd4. There are 1958 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 85 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.7503G>A	p.Thr2501Thr	synonymous_variant	Exon 39 of 66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.7506G>A	p.Thr2502Thr	synonymous_variant	Exon 37 of 64		XP_016880204.1
MYO15A	XM_017024714.3	c.7443G>A	p.Thr2481Thr	synonymous_variant	Exon 36 of 63		XP_016880203.1
LOC124903944	XR_007065652.1	n.377+464C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.7503G>A	p.Thr2501Thr	synonymous_variant	Exon 39 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4176 AN: 152116 Hom.: 85 Cov.: 32

Gnomad AFR AF: 0.00833

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0492

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0437

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0282 AC: 7019 AN: 249284 AF XY: 0.0279

Gnomad AFR exome AF: 0.00665

Gnomad AMR exome AF: 0.00884

Gnomad ASJ exome AF: 0.0202

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0521

Gnomad NFE exome AF: 0.0442

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0419 AC: 61222 AN: 1461686 Hom.: 1577 Cov.: 34 AF XY: 0.0405 AC XY: 29472 AN XY: 727146

African (AFR) AF: 0.00588 AC: 197 AN: 33480

American (AMR) AF: 0.00950 AC: 425 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 523 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00488 AC: 421 AN: 86258

European-Finnish (FIN) AF: 0.0524 AC: 2789 AN: 53230

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5768

European-Non Finnish (NFE) AF: 0.0492 AC: 54762 AN: 1111996

Other (OTH) AF: 0.0344 AC: 2075 AN: 60396

GnomAD4 genome AF: 0.0274 AC: 4176 AN: 152232 Hom.: 85 Cov.: 32 AF XY: 0.0263 AC XY: 1958 AN XY: 74430

African (AFR) AF: 0.00831 AC: 345 AN: 41540

American (AMR) AF: 0.0126 AC: 193 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.0492 AC: 522 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0438 AC: 2975 AN: 67990

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0387 Hom.: 369

Bravo AF: 0.0248

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0402

EpiControl AF: 0.0382

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Sep 25, 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. -

-

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

Thr2501Thr in Exon 39 of MYO15A: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 4.3% (286/6722) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs16960961). -

not provided Benign:3

Mar 15, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

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	-0.72
CADD	Benign	8.3
DANN	Benign	0.69
PhyloP100		2.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs16960961; hg19: chr17-18054453; COSMIC: COSV52767593; COSMIC: COSV52767593;