rs143687204

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_012208.4(HARS2):c.324T>C(p.Tyr108=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,613,586 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 10 hom. )

Consequence

HARS2
NM_012208.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.365

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 5-140694205-T-C is Benign according to our data. Variant chr5-140694205-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 137534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140694205-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=0.365 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0023 (350/152348) while in subpopulation AMR AF= 0.00392 (60/15306). AF 95% confidence interval is 0.00315. There are 0 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HARS2	NM_012208.4 linkuse as main transcript	c.324T>C	p.Tyr108=	synonymous_variant	4/13	ENST00000230771.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS2	ENST00000230771.9 linkuse as main transcript	c.324T>C	p.Tyr108=	synonymous_variant	4/13	1	NM_012208.4	A1	P49590-1

Frequencies

GnomAD3 genomes

AF:

0.00230

AC:

350

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00351

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00217

AC:

546

AN:

251494

Hom.:

AF XY:

0.00209

AC XY:

284

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.000831

Gnomad NFE exome

AF:

0.00355

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00314

AC:

4585

AN:

1461238

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2201

AN XY:

726946

show subpopulations

Gnomad4 AFR exome

AF:

0.000747

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000232

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.00380

Gnomad4 OTH exome

AF:

0.00240

GnomAD4 genome

AF:

0.00230

AC:

350

AN:

152348

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

161

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00351

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00249

EpiCase

AF:

0.00262

EpiControl

AF:

0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Tyr108Tyr in exon 4 of HARS2: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.5% (41/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs143687204). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 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. -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	HARS2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Perrault syndrome 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

HARS2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 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

BayesDel_noAF

Benign

-0.52

CADD

Benign

8.1

DANN

Benign

0.86

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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