chr17-18172182-C-T

Position:

• chr17-18172182-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_016239.4(MYO15A):​c.10242C>T​(p.Phe3414Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00464 in 1,614,192 control chromosomes in the GnomAD database, including 27 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 0.0028 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (24 hom.)
• Consequence: MYO15A NM_016239.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.61

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]

MYO15A (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 17-18172182-C-T is Benign according to our data. Variant chr17-18172182-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178452.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr17-18172182-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.10242C>T	p.Phe3414Phe	synonymous_variant	64/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.10245C>T	p.Phe3415Phe	synonymous_variant	62/64		XP_016880204.1
MYO15A	XM_017024714.3	c.10182C>T	p.Phe3394Phe	synonymous_variant	61/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.10242C>T	p.Phe3414Phe	synonymous_variant	64/66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 425 AN: 152208 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00293 AC: 730 AN: 249468 Hom.: 3 AF XY: 0.00288 AC XY: 390 AN XY: 135358

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00134

Gnomad FIN exome AF: 0.00130

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00495

GnomAD4 exome AF: 0.00483 AC: 7065 AN: 1461866 Hom.: 24 Cov.: 31 AF XY: 0.00471 AC XY: 3428 AN XY: 727228

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00582

Gnomad4 OTH exome AF: 0.00445

GnomAD4 genome AF: 0.00279 AC: 425 AN: 152326 Hom.: 3 Cov.: 32 AF XY: 0.00244 AC XY: 182 AN XY: 74468

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00485

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00323 Hom.: 0

Bravo AF: 0.00292

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000472 AC: 2

ESP6500EA AF: 0.00414 AC: 35

ExAC AF: 0.00281 AC: 340

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00492

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	MYO15A: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2018	This variant is associated with the following publications: (PMID: 24498627) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Phe3414Phe in Exon 64 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 0.4% (27/6864) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.12
CADD	Benign	0.67
DANN	Uncertain	0.97
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.41	D
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.19	D
MVP		0.25
ClinPred		0.011	T
GERP RS		-3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs188485743; hg19: chr17-18075496;