rs76468019

Positions:

• chr17-18122213-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016239.4(MYO15A):​c.3413A>G​(p.Gln1138Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,613,148 control chromosomes in the GnomAD database, including 300 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0052 (229 hom.)
• Consequence: MYO15A NM_016239.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.510

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018774569).
• BP6: Variant 17-18122213-A-G is Benign according to our data. Variant chr17-18122213-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 226784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-18122213-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0995 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4	c.3413A>G	p.Gln1138Arg	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.3413A>G	p.Gln1138Arg	missense_variant	2/66		NM_016239.4	ENSP00000495481.1
MYO15A	ENST00000583079.1	n.3046A>G		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2910 AN: 152182 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.107

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.00837

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.0143

GnomAD3 exomes AF: 0.0139 AC: 3447 AN: 248824 Hom.: 132 AF XY: 0.0125 AC XY: 1689 AN XY: 135266

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.113

Gnomad SAS exome AF: 0.00549

Gnomad FIN exome AF: 0.00779

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00778

GnomAD4 exome AF: 0.00523 AC: 7633 AN: 1460848 Hom.: 229 Cov.: 44 AF XY: 0.00508 AC XY: 3690 AN XY: 726714

Gnomad4 AFR exome AF: 0.0498

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00233

Gnomad4 EAS exome AF: 0.0858

Gnomad4 SAS exome AF: 0.00546

Gnomad4 FIN exome AF: 0.00811

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0191 AC: 2910 AN: 152300 Hom.: 71 Cov.: 33 AF XY: 0.0192 AC XY: 1433 AN XY: 74468

Gnomad4 AFR AF: 0.0484

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.107

Gnomad4 SAS AF: 0.00869

Gnomad4 FIN AF: 0.00837

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.00760 Hom.: 46

Bravo AF: 0.0214

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0425 AC: 173

ESP6500EA AF: 0.000958 AC: 8

ExAC AF: 0.0141 AC: 1703

Asia WGS AF: 0.0410 AC: 144 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2015	p.Gln1138Arg in exon 2 of MYO15A: This variant is not expected to have clinical significance because it has been identified in 10.9% (939/8600) of East Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs76468019). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive nonsyndromic hearing loss 3 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	0.18
DANN	Benign	0.19
DEOGEN2	Benign	0.0094	T;T;T
Eigen	Benign	-2.6
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.17	T;.;T
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	.;L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.020	.;N;.
REVEL	Benign	0.16
Sift	Benign	0.51	.;T;.
Sift4G	Benign	0.89	T;T;.
Polyphen		0.0	.;B;B
Vest4		0.014
ClinPred		0.0097	T
GERP RS		-3.5
Varity_R		0.029
gMVP		0.12

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: rs76468019; hg19: chr17-18025527; COSMIC: COSV52753815;