rs58302597

Positions:

• chr5-140674672-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000504156.7(HARS1):​c.1458+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 1,613,788 control chromosomes in the GnomAD database, including 42,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3343 hom., cov: 33)
  • Exomes 𝑓: 0.23 (39340 hom.)
• Consequence: HARS1 ENST00000504156.7 splice_region, intron
• Scores: Splicing: ADA: 0.00003999
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.121

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-140674672-C-T is Benign according to our data. Variant chr5-140674672-C-T is described in ClinVar as [Benign]. Clinvar id is 226650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-140674672-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HARS1	NM_002109.6	c.1458+7G>A		splice_region_variant, intron_variant		ENST00000504156.7	NP_002100.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7	c.1458+7G>A		splice_region_variant, intron_variant		1	NM_002109.6	ENSP00000425634	P3

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29334 AN: 152124 Hom.: 3327 Cov.: 33

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.212

Gnomad EAS AF: 0.304

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.163

Gnomad NFE AF: 0.231

Gnomad OTH AF: 0.207

GnomAD3 exomes AF: 0.237 AC: 59589 AN: 251312 Hom.: 7473 AF XY: 0.239 AC XY: 32490 AN XY: 135832

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.306

Gnomad SAS exome AF: 0.255

Gnomad FIN exome AF: 0.272

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.238

GnomAD4 exome AF: 0.229 AC: 334900 AN: 1461546 Hom.: 39340 Cov.: 35 AF XY: 0.231 AC XY: 167614 AN XY: 727096

Gnomad4 AFR exome AF: 0.0748

Gnomad4 AMR exome AF: 0.247

Gnomad4 ASJ exome AF: 0.207

Gnomad4 EAS exome AF: 0.296

Gnomad4 SAS exome AF: 0.252

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.227

Gnomad4 OTH exome AF: 0.229

GnomAD4 genome AF: 0.193 AC: 29359 AN: 152242 Hom.: 3343 Cov.: 33 AF XY: 0.194 AC XY: 14473 AN XY: 74426

Gnomad4 AFR AF: 0.0783

Gnomad4 AMR AF: 0.232

Gnomad4 ASJ AF: 0.212

Gnomad4 EAS AF: 0.304

Gnomad4 SAS AF: 0.252

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.231

Gnomad4 OTH AF: 0.212

Alfa AF: 0.209 Hom.: 1565

Bravo AF: 0.183

Asia WGS AF: 0.318 AC: 1105 AN: 3478

EpiCase AF: 0.222

EpiControl AF: 0.217

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	Apr 14, 2015	c.1458+7G>A in intron 12 of HARS: This variant is not expected to have clinical significance because it has been identified in 24% (16069/50639) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs58302597). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Usher syndrome type 3B Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.93
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs58302597; hg19: chr5-140054257; COSMIC: COSV56906696; COSMIC: COSV56906696;