rs146754758

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016239.4(MYO15A):c.3658G>A(p.Gly1220Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000854 in 1,613,198 control chromosomes in the GnomAD database, including 19 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1220E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00081 ( 13 hom. )

Consequence

MYO15A
NM_016239.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.870

Variant links:

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 links:

MYO15A (HGNC:):

MYO15A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00341475).

BP6

Variant 17-18124531-G-A is Benign according to our data. Variant chr17-18124531-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164513.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00129 (196/152312) while in subpopulation EAS AF= 0.0339 (176/5190). AF 95% confidence interval is 0.0298. There are 6 homozygotes in gnomad4. There are 122 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYO15A	NM_016239.4 linkuse as main transcript	c.3658G>A	p.Gly1220Arg	missense_variant	3/66	ENST00000647165.2	NP_057323.3	Q9UKN7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYO15A	ENST00000647165.2 linkuse as main transcript	c.3658G>A	p.Gly1220Arg	missense_variant	3/66		NM_016239.4	ENSP00000495481.1	Q9UKN7-1
MYO15A	ENST00000651088.1 linkuse as main transcript	c.199G>A	p.Gly67Arg	missense_variant	2/2			ENSP00000498988.1	A0A494C1B3
MYO15A	ENST00000583079.1 linkuse as main transcript	n.5364G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.00128

AC:

195

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0336

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00267

AC:

660

AN:

247636

Hom.:

AF XY:

0.00242

AC XY:

326

AN XY:

134608

show subpopulations

Gnomad AFR exome

AF:

0.0000650

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0335

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000444

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000809

AC:

1182

AN:

1460886

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

595

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0223

Gnomad4 SAS exome

AF:

0.00163

Gnomad4 FIN exome

AF:

0.0000381

Gnomad4 NFE exome

AF:

0.0000531

Gnomad4 OTH exome

AF:

0.00149

GnomAD4 genome

AF:

0.00129

AC:

196

AN:

152312

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0339

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00240

Hom.:

Bravo

AF:

0.00171

ExAC

AF:

0.00269

AC:

326

Asia WGS

AF:

0.00924

AC:

AN:

3476

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 3

Uncertain:1Benign: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	case-control	Molecular Diagnosis Center for Deafness	-	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2013	Gly1220Arg in exon 3 of MYO15A: This variant is not expected to have clinical si gnificance because it has been identified in 1% (22/2178) of chromosomes by the 1000 Genomes Project (dbSNP rs146754758) and most mammals, including other prima tes, carry an arginine (Arg) at this position. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2019	This variant is associated with the following publications: (PMID: 23865914) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.30

CADD

Benign

6.7

DANN

Benign

0.50

DEOGEN2

Benign

0.023

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.035

T;.;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

-1.5

.;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

.;N;.

REVEL

Benign

0.21

Sift

Benign

1.0

.;T;.

Sift4G

Benign

0.93

T;T;.

Polyphen

0.0010

.;B;B

Vest4

0.15

MVP

0.25

ClinPred

0.0070

GERP RS

0.65

Varity_R

0.039

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over