rs140140417

Positions:

• chr17-18155154-G-A

Variant summary

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

The NM_016239.4(MYO15A):​c.8269G>A​(p.Val2757Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,966 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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: 0.0019 (9 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.13

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0064539015).
• BP6: Variant 17-18155154-G-A is Benign according to our data. Variant chr17-18155154-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164555.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr17-18155154-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.8269G>A	p.Val2757Met	missense_variant	46/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.8269G>A	p.Val2757Met	missense_variant	46/66		NM_016239.4	ENSP00000495481.1

Frequencies

GnomAD3 genomes AF: 0.00157 AC: 239 AN: 152222 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00233 AC: 579 AN: 248928 Hom.: 2 AF XY: 0.00237 AC XY: 320 AN XY: 135192

Gnomad AFR exome AF: 0.000454

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00468

Gnomad EAS exome AF: 0.000111

Gnomad SAS exome AF: 0.00562

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00188 AC: 2747 AN: 1461626 Hom.: 9 Cov.: 32 AF XY: 0.00205 AC XY: 1491 AN XY: 727106

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00241

Gnomad4 ASJ exome AF: 0.00612

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00528

Gnomad4 FIN exome AF: 0.000207

Gnomad4 NFE exome AF: 0.00155

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152340 Hom.: 1 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74500

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00181

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00224 Hom.: 0

Bravo AF: 0.00189

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00213 AC: 18

ExAC AF: 0.00226 AC: 274

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00278

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MYO15A: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 08, 2019	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 30, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 15, 2016

p.Val2757Met in exon 46 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, hedgehog, elephant, hyrax and platypus have a methionine (Met) at this position despite high nearby amino acid conservation. In addition, this variant has been identified in 0.6% (94/16282) of South Asian chromosomes including 1 ho mozygote by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs140140417). -

MYO15A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2020

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.047	T;T;T;.;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T;.;T;T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.0065	T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.5	.;L;L;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	.;N;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.048	.;D;.;.;.
Sift4G	Benign	0.13	T;T;.;D;.
Polyphen		0.15	.;B;B;.;.
Vest4		0.28
MVP		0.60
ClinPred		0.0048	T
GERP RS		-0.24
Varity_R		0.077
gMVP		0.45

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: rs140140417; hg19: chr17-18058468;