rs117021471

Variant names:

• chr17-18136486-G-A
• rs117021471
• NM_016239.4:c.4655+11G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_016239.4(MYO15A):​c.4655+11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,626 control chromosomes in the GnomAD database, including 11 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 0.0016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (10 hom.)
• Consequence: MYO15A NM_016239.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.586

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 17-18136486-G-A is Benign according to our data. Variant chr17-18136486-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164521.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}. Variant chr17-18136486-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00157 (239/152274) while in subpopulation EAS AF= 0.0247 (128/5180). AF 95% confidence interval is 0.0212. There are 1 homozygotes in gnomad4. There are 140 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.4655+11G>A		intron_variant	Intron 14 of 65	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.4655+11G>A		intron_variant	Intron 14 of 65		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00763

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00285 AC: 709 AN: 248990 Hom.: 2 AF XY: 0.00277 AC XY: 374 AN XY: 135148

Gnomad AFR exome AF: 0.000322

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0255

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00756

Gnomad NFE exome AF: 0.000557

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00111 AC: 1623 AN: 1461352 Hom.: 10 Cov.: 32 AF XY: 0.00110 AC XY: 802 AN XY: 727010

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0225

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00785

Gnomad4 NFE exome AF: 0.000152

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00157 AC: 239 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74448

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0247

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00763

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000732 Hom.: 0

Bravo AF: 0.00138

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:1

Apr 17, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

4655+11G>A in Intron 14 of MYO15A: This variant is not expected to have clinical significance because has been identified in 2.6% (223/8612) of East Asian chrom osomes including 1 homozygote by the by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs117021471). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.011
DANN	Benign	0.49

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: rs117021471; hg19: chr17-18039800;