rs2230361

Positions:

• chr5-140677950-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002109.6(HARS1):​c.588C>T​(p.Cys196=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.857

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]

ACMG classification

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	UniProt
HARS1	NM_002109.6	c.588C>T	p.Cys196=	synonymous_variant	6/13	ENST00000504156.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HARS1	ENST00000504156.7	c.588C>T	p.Cys196=	synonymous_variant	6/13	1	NM_002109.6	P3

Frequencies

GnomAD3 genomes AF: 0.0744 AC: 11269 AN: 151540 Hom.: 488 Cov.: 31

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

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.: 29 AF XY: 0.0781 AC XY: 56681 AN XY: 725828

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.: 31 AF XY: 0.0760 AC XY: 5625 AN XY: 74058

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

Submissions by phenotype

not specified Benign:2

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. -
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). -

Usher syndrome type 3B Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
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

Other links and lift over

dbSNP: rs2230361; hg19: chr5-140057535; COSMIC: COSV56910222; COSMIC: COSV56910222;