rs150128469

Positions:

• chr17-18138951-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_016239.4(MYO15A):​c.5133+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,610,008 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.440

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-18138951-A-G is Benign according to our data. Variant chr17-18138951-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178442.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr17-18138951-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.5133+15A>G		intron_variant		ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.5133+15A>G		intron_variant			NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000646238.1	n.397+15A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152212 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00265 AC: 637 AN: 240162 Hom.: 4 AF XY: 0.00272 AC XY: 354 AN XY: 130336

Gnomad AFR exome AF: 0.000758

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000711

Gnomad FIN exome AF: 0.0000483

Gnomad NFE exome AF: 0.00331

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.00299 AC: 4359 AN: 1457678 Hom.: 16 Cov.: 30 AF XY: 0.00303 AC XY: 2198 AN XY: 724712

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000947

Gnomad4 FIN exome AF: 0.0000378

Gnomad4 NFE exome AF: 0.00306

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152330 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74488

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000980

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00506 Hom.: 1

Bravo AF: 0.00238

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	MYO15A: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

5133+15A>G in Intron 18 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 0.4% (26/6846) of European American chromosome s from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.w ashington.edu/EVS; dbSNP rs150128469). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.017
DANN	Benign	0.29

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: rs150128469; hg19: chr17-18042265;