rs201028204

Positions:

• chr17-18173823-C-T

Variant summary

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

The NM_016239.4(MYO15A):​c.10393C>T​(p.Arg3465Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000952 in 1,614,038 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00097 (6 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.791

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011355877).
• BP6: Variant 17-18173823-C-T is Benign according to our data. Variant chr17-18173823-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 45743.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.10393C>T	p.Arg3465Trp	missense_variant	65/66	ENST00000647165.2	NP_057323.3
MYO15A	XM_017024715.3	c.10396C>T	p.Arg3466Trp	missense_variant	63/64		XP_016880204.1
MYO15A	XM_017024714.3	c.10333C>T	p.Arg3445Trp	missense_variant	62/63		XP_016880203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.10393C>T	p.Arg3465Trp	missense_variant	65/66		NM_016239.4	ENSP00000495481	P1
	ENST00000577847.1	n.393-1078G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000801 AC: 122 AN: 152258 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00117 AC: 291 AN: 248314 Hom.: 3 AF XY: 0.00131 AC XY: 177 AN XY: 135010

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000406

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00337

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000993

GnomAD4 exome AF: 0.000968 AC: 1415 AN: 1461662 Hom.: 6 Cov.: 29 AF XY: 0.00105 AC XY: 763 AN XY: 727142

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00195

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00352

Gnomad4 FIN exome AF: 0.00117

Gnomad4 NFE exome AF: 0.000819

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152376 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74518

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000987 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000604 AC: 5

ExAC AF: 0.00125 AC: 151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	MYO15A: PM5, BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2019	- -

Autosomal recessive nonsyndromic hearing loss 3 Uncertain: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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2015

p.Arg3465Trp in Exon 65 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 0.36% (60/16502) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs201028204). -

MYO15A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 08, 2021

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	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.12	T;D;D;.
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.85	T;.;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	.;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-4.7	.;D;.;.
REVEL	Benign	0.21
Sift	Benign	0.19	.;T;.;.
Sift4G	Uncertain	0.042	D;D;.;D
Polyphen		0.073	.;B;B;.
Vest4		0.34
MVP		0.56
ClinPred		0.060	T
GERP RS		0.14
Varity_R		0.10
gMVP		0.59

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: rs201028204; hg19: chr17-18077137;