rs147458358

chr17-18163805-A-G

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.9754A>G(p.Asn3252Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,614,074 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3252S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (11 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.868

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 (MetaRNN=0.0043999553).
• BP6: Variant 17-18163805-A-G is Benign according to our data. Variant chr17-18163805-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164566.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5, Benign=4}. Variant chr17-18163805-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00183 (2676/1461754) while in subpopulation MID AF= 0.0205 (118/5768). AF 95% confidence interval is 0.0175. There are 11 homozygotes in gnomad4_exome. There are 1407 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.9754A>G	p.Asn3252Asp	missense_variant	60/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.9757A>G	p.Asn3253Asp	missense_variant	58/64
MYO15A	XM_017024714.3	c.9694A>G	p.Asn3232Asp	missense_variant	57/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.9754A>G	p.Asn3252Asp	missense_variant	60/66		NM_016239.4	P1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00251

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00242 AC: 603 AN: 249064 Hom.: 3 AF XY: 0.00274 AC XY: 371 AN XY: 135158

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00835

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00400

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00256

Gnomad OTH exome AF: 0.00710

GnomAD4 exome AF: 0.00183 AC: 2676 AN: 1461754 Hom.: 11 Cov.: 32 AF XY: 0.00193 AC XY: 1407 AN XY: 727152

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00880

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00380

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.00153

Gnomad4 OTH exome AF: 0.00316

GnomAD4 genome AF: 0.00191 AC: 291 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.00197 AC XY: 147 AN XY: 74470

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00251

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00295 Hom.: 2

Bravo AF: 0.00243

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000246 AC: 1

ESP6500EA AF: 0.00298 AC: 25

ExAC AF: 0.00235 AC: 284

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00374

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Asn3252Asp in Exon 60 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.4% (26/6804) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs147458358). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2016	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MYO15A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

MYO15A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	0.15
Dann	Benign	0.87
DEOGEN2	Benign	0.0029	T;T;T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0074	N
LIST_S2	Benign	0.20	T;.;T;T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.0044	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
Sift4G	Benign	1.0	T;T;.;T;.;T
Polyphen		0.0	.;B;B;.;.;.
Vest4		0.23
MVP		0.38
ClinPred		0.0061	T
GERP RS		-2.5
Varity_R		0.058
gMVP		0.38

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: rs147458358; hg19: chr17-18067119; COSMIC: COSV99068560; COSMIC: COSV99068560;