rs200456053

Positions:

• chr17-18173833-G-A
• chr17-18173833-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_016239.4(MYO15A):​c.10403G>A​(p.Arg3468Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000294 in 1,613,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. R3468W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (1 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.61

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0093713105).
• BP6: Variant 17-18173833-G-A is Benign according to our data. Variant chr17-18173833-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227631.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYO15A	NM_016239.4	c.10403G>A	p.Arg3468Gln	missense_variant	65/66	ENST00000647165.2
MYO15A	XM_017024715.3	c.10406G>A	p.Arg3469Gln	missense_variant	63/64
MYO15A	XM_017024714.3	c.10343G>A	p.Arg3448Gln	missense_variant	62/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYO15A	ENST00000647165.2	c.10403G>A	p.Arg3468Gln	missense_variant	65/66		NM_016239.4	P1
	ENST00000577847.1	n.393-1088C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000601 AC: 149 AN: 248118 Hom.: 0 AF XY: 0.000682 AC XY: 92 AN XY: 134940

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00627

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000287 AC: 420 AN: 1460976 Hom.: 1 Cov.: 29 AF XY: 0.000315 AC XY: 229 AN XY: 726820

Gnomad4 AFR exome AF: 0.000389

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00628

Gnomad4 EAS exome AF: 0.000857

Gnomad4 SAS exome AF: 0.000475

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000255 AC XY: 19 AN XY: 74498

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000420 Hom.: 0

Bravo AF: 0.000404

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.000362 AC: 3

ExAC AF: 0.000546 AC: 66

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 28, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2021	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain: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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 24, 2015

p.Arg3468Gln in exon 65 of MYO15A: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 6 mammals (including mouse, rat, and hedgehog) have a glutamine (Gln) at this position despite high nearby amino acid conservation. In addition, computa tional prediction tools do not suggest a high likelihood of impact to the protei n. It has also been identified in 0.3% (21/8552) of East Asian chromosomes by th e Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20 0456053). -

MYO15A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 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	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T;.;T;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0094	T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.31	T
Sift4G	Uncertain	0.049	D;D;.;T
Polyphen		0.60	.;P;P;.
Vest4		0.23
MVP		0.74
ClinPred		0.054	T
GERP RS		2.6
Varity_R		0.080
gMVP		0.43

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: rs200456053; hg19: chr17-18077147; COSMIC: COSV99230783; COSMIC: COSV99230783;