chr17-18118854-G-A

Variant names:

• chr17-18118854-G-A
• rs144909486
• NM_016239.4:c.54G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_016239.4(MYO15A):​c.54G>A​(p.Lys18Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,612,666 control chromosomes in the GnomAD database, including 5 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 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 3.09

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 17-18118854-G-A is Benign according to our data. Variant chr17-18118854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260700.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=5}. Variant chr17-18118854-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=3.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00234 (3414/1460344) while in subpopulation NFE AF= 0.00265 (2950/1111372). AF 95% confidence interval is 0.00257. There are 5 homozygotes in gnomad4_exome. There are 1672 alleles in male gnomad4_exome subpopulation. Median coverage is 35. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.54G>A	p.Lys18Lys	synonymous_variant	Exon 2 of 66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.54G>A	p.Lys18Lys	synonymous_variant	Exon 2 of 66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00218

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00163 AC: 397 AN: 244140 Hom.: 0 AF XY: 0.00167 AC XY: 222 AN XY: 133032

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.000702

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00237

Gnomad OTH exome AF: 0.00134

GnomAD4 exome AF: 0.00234 AC: 3414 AN: 1460344 Hom.: 5 Cov.: 35 AF XY: 0.00230 AC XY: 1672 AN XY: 726366

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000809

Gnomad4 ASJ exome AF: 0.00541

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00265

Gnomad4 OTH exome AF: 0.00230

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00128 AC XY: 95 AN XY: 74486

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00218

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Jun 03, 2019

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 24498627) -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MYO15A: BP4, BS1 -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 25, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Lys18Lys in exon 02 of MYO15A: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 0.2% (134/56718) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNP rs144909486). -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1

Apr 27, 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). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Benign	0.54

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: rs144909486; hg19: chr17-18022168;