rs147288996

Variant names:

Variant summary

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

The NM_002109.6(HARS1):c.614G>A(p.Gly205Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00223 in 1,607,964 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0022 ( 12 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

HARS1 (HGNC:4816): (histidyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is a cytoplasmic enzyme which belongs to the class II family of aminoacyl-tRNA synthetases. The enzyme is responsible for the synthesis of histidyl-transfer RNA, which is essential for the incorporation of histidine into proteins. The gene is located in a head-to-head orientation with HARSL on chromosome five, where the homologous genes share a bidirectional promoter. The gene product is a frequent target of autoantibodies in the human autoimmune disease polymyositis/dermatomyositis. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

HARS1 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=0.010127872).

BP6

Variant 5-140677924-C-T is Benign according to our data. Variant chr5-140677924-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140677924-C-T is described in Lovd as [Benign]. Variant chr5-140677924-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00276 (419/151910) while in subpopulation SAS AF= 0.00313 (15/4794). AF 95% confidence interval is 0.00193. There are 3 homozygotes in gnomad4. There are 295 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS1	NM_002109.6 link	c.614G>A	p.Gly205Asp	missense_variant	Exon 6 of 13	ENST00000504156.7	NP_002100.2	P12081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7 link	c.614G>A	p.Gly205Asp	missense_variant	Exon 6 of 13	1	NM_002109.6	ENSP00000425634.1		P12081-1

Frequencies

GnomAD3 genomes

AF:

0.00276

AC:

419

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000329

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00313

Gnomad FIN

AF:

0.0211

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00284

AC:

715

AN:

251372

Hom.:

AF XY:

0.00283

AC XY:

384

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.000596

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.00226

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00218

AC:

3167

AN:

1456054

Hom.:

Cov.:

AF XY:

0.00216

AC XY:

1566

AN XY:

724832

show subpopulations

Gnomad4 AFR exome

AF:

0.000360

Gnomad4 AMR exome

AF:

0.000514

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00137

Gnomad4 FIN exome

AF:

0.0138

Gnomad4 NFE exome

AF:

0.00189

Gnomad4 OTH exome

AF:

0.00201

GnomAD4 genome

AF:

0.00276

AC:

419

AN:

151910

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

295

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.000328

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00313

Gnomad4 FIN

AF:

0.0211

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00126

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00257

AC:

312

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00255

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HARS1: BS2 -

Sep 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22930593, 26264438) -

not specified

Benign:1

Mar 17, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Gly205Asp in exon 6 of HARS: This variant is not expected to have clinical sig nificance because it has been identified in 1.7% (115/6610) of Finnish chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs147288996). -

Usher syndrome type 3B

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

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

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

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

MetaRNN

Benign

0.010

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

MetaSVM

Benign

-0.29

MutationAssessor

Benign

1.8

.;.;L;L;.;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.7

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

REVEL

Uncertain

0.41

Sift

Uncertain

0.027

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

Sift4G

Uncertain

0.018

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

Polyphen

0.73, 1.0, 0.73

.;P;D;D;.;.;.;P

Vest4

0.71

MVP

0.89

MPC

1.2

ClinPred

0.054

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.94

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