5-140691291-G-T

Position:

chr5-140691291-G-T

Variant summary

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

The NM_002109.6(HARS1):c.14C>A(p.Ala5Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00758 in 1,605,400 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0058 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0078 ( 50 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 3.96

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037422776).

BP6

Variant 5-140691291-G-T is Benign according to our data. Variant chr5-140691291-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472991.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2, Benign=4}. Variant chr5-140691291-G-T is described in Lovd as [Benign]. Variant chr5-140691291-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00582 (885/152110) while in subpopulation AMR AF= 0.0091 (139/15274). AF 95% confidence interval is 0.00814. There are 4 homozygotes in gnomad4. There are 417 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS1	NM_002109.6 link	c.14C>A	p.Ala5Glu	missense_variant	1/13	ENST00000504156.7	NP_002100.2	P12081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7 link	c.14C>A	p.Ala5Glu	missense_variant	1/13	1	NM_002109.6	ENSP00000425634.1		P12081-1

Frequencies

GnomAD3 genomes

AF:

0.00581

AC:

883

AN:

151992

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00167

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00911

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000831

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00869

Gnomad OTH

AF:

0.0120

GnomAD3 exomes

AF:

0.00543

AC:

1321

AN:

243488

Hom.:

AF XY:

0.00546

AC XY:

723

AN XY:

132396

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00614

Gnomad ASJ exome

AF:

0.00758

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00129

Gnomad FIN exome

AF:

0.00188

Gnomad NFE exome

AF:

0.00790

Gnomad OTH exome

AF:

0.00937

GnomAD4 exome

AF:

0.00776

AC:

11276

AN:

1453290

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

5538

AN XY:

723214

show subpopulations

Gnomad4 AFR exome

AF:

0.000778

Gnomad4 AMR exome

AF:

0.00695

Gnomad4 ASJ exome

AF:

0.00904

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00136

Gnomad4 FIN exome

AF:

0.00256

Gnomad4 NFE exome

AF:

0.00904

Gnomad4 OTH exome

AF:

0.00701

GnomAD4 genome

AF:

0.00582

AC:

885

AN:

152110

Hom.:

Cov.:

AF XY:

0.00561

AC XY:

417

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00166

Gnomad4 AMR

AF:

0.00910

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000832

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00872

Gnomad4 OTH

AF:

0.0119

Alfa

AF:

0.00774

Hom.:

Bravo

AF:

0.00635

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0105

AC:

ExAC

AF:

0.00563

AC:

684

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00993

EpiControl

AF:

0.00748

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2018	This variant is associated with the following publications: (PMID: 22930593) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	HARS1: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 02, 2021	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Usher syndrome type 3B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 15, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.026

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

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.76

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

MetaRNN

Benign

0.0037

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

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

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.45

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

REVEL

Benign

0.046

Sift

Benign

0.62

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

Sift4G

Benign

0.81

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

Polyphen

0.32, 0.37

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

Vest4

0.33

MVP

0.53

MPC

0.48

ClinPred

0.0075

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.074

gMVP

0.35

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