rs16960961

chr17-18151139-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016239.4(MYO15A):c.7503G>A(p.Thr2501=) 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:6
• Conservation: PhyloP100: 2.36

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 -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 [Likely_benign]. Clinvar id is 45760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18151139-G-A is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 85 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.7503G>A	p.Thr2501=	synonymous_variant	39/66	ENST00000647165.2
LOC124903944	XR_007065652.1	n.377+464C>T		intron_variant, non_coding_transcript_variant
MYO15A	XM_017024715.3	c.7506G>A	p.Thr2502=	synonymous_variant	37/64
MYO15A	XM_017024714.3	c.7443G>A	p.Thr2481=	synonymous_variant	36/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.7503G>A	p.Thr2501=	synonymous_variant	39/66		NM_016239.4	P1

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

GnomAD3 exomes AF: 0.0282 AC: 7019 AN: 249284 Hom.: 169 AF XY: 0.0279 AC XY: 3776 AN XY: 135264

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 SAS exome AF: 0.00444

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

Gnomad4 AFR exome AF: 0.00588

Gnomad4 AMR exome AF: 0.00950

Gnomad4 ASJ exome AF: 0.0200

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00488

Gnomad4 FIN exome AF: 0.0524

Gnomad4 NFE exome AF: 0.0492

Gnomad4 OTH exome AF: 0.0344

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

Gnomad4 AFR AF: 0.00831

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0492

Gnomad4 NFE AF: 0.0438

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0375 Hom.: 168

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2017	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:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 15, 2019	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs16960961; hg19: chr17-18054453; COSMIC: COSV52767593; COSMIC: COSV52767593;