rs577023485

Positions:

• chr17-18120828-C-A
• chr17-18120828-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016239.4(MYO15A):​c.2028C>A​(p.Pro676=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,173,212 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P676P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0071 (3 hom., cov: 32)
  • Exomes 𝑓: 0.013 (92 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.45

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-18120828-C-A is Benign according to our data. Variant chr17-18120828-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 227636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18120828-C-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.45 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.2028C>A	p.Pro676=	synonymous_variant	2/66	ENST00000647165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.2028C>A	p.Pro676=	synonymous_variant	2/66		NM_016239.4	P1
MYO15A	ENST00000583079.1	n.1661C>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00712 AC: 1049 AN: 147414 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00162

Gnomad ASJ AF: 0.00264

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00824

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.00493

GnomAD3 exomes AF: 0.0110 AC: 30 AN: 2730 Hom.: 0 AF XY: 0.0128 AC XY: 23 AN XY: 1798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00149

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0130 AC: 13353 AN: 1025694 Hom.: 92 Cov.: 32 AF XY: 0.0129 AC XY: 6348 AN XY: 493742

Gnomad4 AFR exome AF: 0.00137

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00299

Gnomad4 EAS exome AF: 0.0000656

Gnomad4 SAS exome AF: 0.00208

Gnomad4 FIN exome AF: 0.0109

Gnomad4 NFE exome AF: 0.0144

Gnomad4 OTH exome AF: 0.00811

GnomAD4 genome AF: 0.00710 AC: 1048 AN: 147518 Hom.: 3 Cov.: 32 AF XY: 0.00644 AC XY: 463 AN XY: 71854

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00162

Gnomad4 ASJ AF: 0.00264

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00824

Gnomad4 NFE AF: 0.0124

Gnomad4 OTH AF: 0.00439

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00654

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MYO15A: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2019	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -
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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 28, 2015

p.Pro676Pro in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.3% (1/374) of S outh Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs577023485). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.75
DANN	Benign	0.74

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: rs577023485; hg19: chr17-18024142;