5-140677950-G-A

Position:

chr5-140677950-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002109.6(HARS1):c.588C>T(p.Cys196Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0773 in 1,610,300 control chromosomes in the GnomAD database, including 5,313 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.074 ( 488 hom., cov: 31)

Exomes 𝑓: 0.078 ( 4825 hom. )

Consequence

HARS1
NM_002109.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.857

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:

HARS1 (HGNC:):

HARS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.47).

BP6

Variant 5-140677950-G-A is Benign according to our data. Variant chr5-140677950-G-A is described in ClinVar as [Benign]. Clinvar id is 226651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140677950-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.857 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS1	NM_002109.6 linkuse as main transcript	c.588C>T	p.Cys196Cys	synonymous_variant	6/13	ENST00000504156.7	NP_002100.2	P12081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7 linkuse as main transcript	c.588C>T	p.Cys196Cys	synonymous_variant	6/13	1	NM_002109.6	ENSP00000425634.1		P12081-1

Frequencies

GnomAD3 genomes

AF:

0.0744

AC:

11269

AN:

151540

Hom.:

488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0646

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.0897

Gnomad ASJ

AF:

0.0367

Gnomad EAS

AF:

0.00270

Gnomad SAS

AF:

0.0946

Gnomad FIN

AF:

0.0791

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0805

Gnomad OTH

AF:

0.0691

GnomAD3 exomes

AF:

0.0796

AC:

20016

AN:

251300

Hom.:

1030

AF XY:

0.0804

AC XY:

10924

AN XY:

135836

show subpopulations

Gnomad AFR exome

AF:

0.0615

Gnomad AMR exome

AF:

0.129

Gnomad ASJ exome

AF:

0.0328

Gnomad EAS exome

AF:

0.00169

Gnomad SAS exome

AF:

0.105

Gnomad FIN exome

AF:

0.0866

Gnomad NFE exome

AF:

0.0760

Gnomad OTH exome

AF:

0.0779

GnomAD4 exome

AF:

0.0776

AC:

113172

AN:

1458642

Hom.:

4825

Cov.:

AF XY:

0.0781

AC XY:

56681

AN XY:

725828

show subpopulations

Gnomad4 AFR exome

AF:

0.0590

Gnomad4 AMR exome

AF:

0.123

Gnomad4 ASJ exome

AF:

0.0316

Gnomad4 EAS exome

AF:

0.000806

Gnomad4 SAS exome

AF:

0.106

Gnomad4 FIN exome

AF:

0.0868

Gnomad4 NFE exome

AF:

0.0781

Gnomad4 OTH exome

AF:

0.0689

GnomAD4 genome

AF:

0.0743

AC:

11264

AN:

151658

Hom.:

488

Cov.:

AF XY:

0.0760

AC XY:

5625

AN XY:

74058

show subpopulations

Gnomad4 AFR

AF:

0.0644

Gnomad4 AMR

AF:

0.0896

Gnomad4 ASJ

AF:

0.0367

Gnomad4 EAS

AF:

0.00271

Gnomad4 SAS

AF:

0.0945

Gnomad4 FIN

AF:

0.0791

Gnomad4 NFE

AF:

0.0805

Gnomad4 OTH

AF:

0.0684

Alfa

AF:

0.0763

Hom.:

328

Bravo

AF:

0.0733

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.0725

EpiControl

AF:

0.0710

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 04, 2016	p.Cys196Cys in exon 6 of HARS: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 8% (9547/121084) of pan ethnic chromosomes including over 400 homozygous individuals by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2230361). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Usher syndrome type 3B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.80

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