rs186043734

Positions:

chr5-140691655-C-G

Variant summary

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

The ENST00000230771.9(HARS2):c.7C>G(p.Leu3Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,549,654 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.0028 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 11 hom. )

Consequence

HARS2
ENST00000230771.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.770

Variant links:

Genes affected

HARS2 (HGNC:4817): (histidyl-tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]

HARS2 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=0.0035395622).

BP6

Variant 5-140691655-C-G is Benign according to our data. Variant chr5-140691655-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137536.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=2}. Variant chr5-140691655-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00276 (421/152360) while in subpopulation SAS AF= 0.0031 (15/4832). AF 95% confidence interval is 0.00193. There are 3 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS2	NM_012208.4 linkuse as main transcript	c.7C>G	p.Leu3Val	missense_variant	1/13	ENST00000230771.9	NP_036340.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS2	ENST00000230771.9 linkuse as main transcript	c.7C>G	p.Leu3Val	missense_variant	1/13	1	NM_012208.4	ENSP00000230771	A1	P49590-1

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

421

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00289

AC:

445

AN:

153748

Hom.:

AF XY:

0.00260

AC XY:

213

AN XY:

81816

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.000566

Gnomad ASJ exome

AF:

0.000473

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.0181

Gnomad NFE exome

AF:

0.00186

Gnomad OTH exome

AF:

0.00184

GnomAD4 exome

AF:

0.00215

AC:

3006

AN:

1397294

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

1455

AN XY:

689384

show subpopulations

Gnomad4 AFR exome

AF:

0.000380

Gnomad4 AMR exome

AF:

0.000672

Gnomad4 ASJ exome

AF:

0.000278

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.0137

Gnomad4 NFE exome

AF:

0.00188

Gnomad4 OTH exome

AF:

0.00197

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152360

Hom.:

Cov.:

AF XY:

0.00397

AC XY:

296

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00310

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00179

Hom.:

Bravo

AF:

0.00125

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000473

AC:

ESP6500EA

AF:

0.000969

AC:

ExAC

AF:

0.000733

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HARS2: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2016	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 06, 2016	p.Leu3Val in exon 1 of HARS2: This variant is not expected to have clinical sign ificance because the leucine (Leu) at this position is not conserved through spe cies, with >5 mammals having a valine (Val) at this position. Furthermore, it h as been in 0.1% (9/6124) of European chromosomes and 0.1% (10/7898) of South Asi an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org, dbSNP rs186043734). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2014	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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.055

T;.;.;T;.;T;T;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.73

.;.;T;T;T;.;T;T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.0035

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;.;.;.;N;N;N;.

MutationTaster

Benign

1.0

D;N;N;N;N;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.030

N;.;.;N;.;.;.;N;N

REVEL

Benign

0.077

Sift

Benign

0.24

T;.;.;T;.;.;.;T;D

Sift4G

Benign

0.68

T;.;.;T;.;.;.;T;.

Polyphen

0.0090

B;.;.;.;.;B;B;.;B

Vest4

0.12

MVP

0.39

MPC

0.15

ClinPred

0.040

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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