17-18120187-A-G

Position:

• chr17-18120187-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016239.4(MYO15A):​c.1387A>G​(p.Met463Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,612,908 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0011 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 2.94

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011315584).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.1387A>G	p.Met463Val	missense_variant	2/66	ENST00000647165.2	NP_057323.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYO15A	ENST00000647165.2	c.1387A>G	p.Met463Val	missense_variant	2/66		NM_016239.4	ENSP00000495481	P1
MYO15A	ENST00000583079.1	n.1020A>G		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 159 AN: 152220 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00127 AC: 315 AN: 248164 Hom.: 1 AF XY: 0.00144 AC XY: 195 AN XY: 135016

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000638

Gnomad ASJ exome AF: 0.00290

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00142 AC: 2076 AN: 1460570 Hom.: 3 Cov.: 36 AF XY: 0.00149 AC XY: 1086 AN XY: 726582

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.000153

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152338 Hom.: 2 Cov.: 33 AF XY: 0.00101 AC XY: 75 AN XY: 74482

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00173

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000234 AC: 1

ESP6500EA AF: 0.00154 AC: 13

ExAC AF: 0.00125 AC: 151

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2021	This variant is associated with the following publications: (PMID: 27375115, 30953472, 25262649, 22736430, 22903915, 30245029) -
Likely 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	May 01, 2024	MYO15A: BP4, BS2 -

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

Apr 25, 2017

p.Met463Val in exon 2 of MYO15A: This variant is not expected to have clinical s ignificance because it has been identified in 0.3% (29/10144) Ashkenazi Jewish c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs201794569). In addition, although this variant was previously reported in a family with hearing loss, it was in cis with a pathogenic loss of function variant that was the likely explanation of the hearing loss in that fam ily (Fattahi 2012). -

MYO15A-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 18, 2019

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	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.015	T;T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.057
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	.;L;L
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.086
Sift	Benign	0.096	.;T;.
Sift4G	Benign	0.091	T;T;.
Polyphen		0.070	.;B;B
Vest4		0.37
MVP		0.33
ClinPred		0.0075	T
GERP RS		5.4
Varity_R		0.17
gMVP		0.64

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: rs201794569; hg19: chr17-18023501;