rs61736946

Positions:

chr5-140697314-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_012208.4(HARS2):c.1105G>C(p.Gly369Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,614,126 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 5 hom. )

Consequence

HARS2
NM_012208.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.55

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013633937).

BP6

Variant 5-140697314-G-C is Benign according to our data. Variant chr5-140697314-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 214547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00256 (390/152248) while in subpopulation AFR AF= 0.00891 (370/41534). AF 95% confidence interval is 0.00816. There are 2 homozygotes in gnomad4. There are 205 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS2	NM_012208.4 linkuse as main transcript	c.1105G>C	p.Gly369Arg	missense_variant	10/13	ENST00000230771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS2	ENST00000230771.9 linkuse as main transcript	c.1105G>C	p.Gly369Arg	missense_variant	10/13	1	NM_012208.4	A1	P49590-1

Frequencies

GnomAD3 genomes

AF:

0.00256

AC:

389

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00891

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000672

AC:

169

AN:

251456

Hom.:

AF XY:

0.000515

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00929

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000301

AC:

440

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000243

AC XY:

177

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0111

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000729

GnomAD4 genome

AF:

0.00256

AC:

390

AN:

152248

Hom.:

Cov.:

AF XY:

0.00275

AC XY:

205

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00891

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000444

Hom.:

Bravo

AF:

0.00309

ESP6500AA

AF:

0.00931

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000832

AC:

101

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Gly369Arg in exon 10 of HARS2: This variant is not expected to have clinical sig nificance because it has been identified in 0.9% (41/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs61736946). -

Perrault syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 01, 2021

- -

HARS2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as 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

0.19

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.66

D;.;.;.;.;.;.;D;D;.;D

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

.;.;.;D;D;D;D;.;D;D;D

M_CAP

Benign

0.050

MetaRNN

Benign

0.014

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

MetaSVM

Uncertain

0.091

MutationAssessor

Pathogenic

3.3

M;.;.;.;.;.;.;M;M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.1

D;.;.;.;.;.;.;.;.;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;.;.;.;.;.;.;.;.;D;D

Sift4G

Pathogenic

0.0010

D;.;.;.;.;.;.;.;.;D;D

Polyphen

0.98

D;.;.;.;.;.;.;D;D;.;D

Vest4

0.64

MVP

0.92

MPC

0.23

ClinPred

0.062

GERP RS

5.7

Varity_R

0.83

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