chr5-140674672-C-T

Variant names:

• chr5-140674672-C-T
• rs58302597
• NM_002109.6:c.1458+7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002109.6(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 NM_002109.6 splice_region, intron
• Scores: Splicing: ADA: 0.00003999
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.121
• Publications: 14 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant Charcot-Marie-Tooth disease type 2W

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Usher syndrome type 3B

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 226650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002109.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	NM_002109.6	MANE Select	c.1458+7G>A		splice_region intron	N/A	NP_002100.2
	HARS1	NM_001258041.3		c.1398+7G>A		splice_region intron	N/A	NP_001244970.1
	HARS1	NM_001289094.2		c.1371+7G>A		splice_region intron	N/A	NP_001276023.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HARS1	ENST00000504156.7	TSL:1 MANE Select	c.1458+7G>A		splice_region intron	N/A	ENSP00000425634.1
	HARS1	ENST00000457527.6	TSL:1	c.1398+7G>A		splice_region intron	N/A	ENSP00000387893.2
	HARS1	ENST00000675204.1		c.1465G>A	p.Glu489Lys	missense	Exon 12 of 12	ENSP00000501643.1

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

GnomAD2 exomes AF: 0.237 AC: 59589 AN: 251312 AF XY: 0.239

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 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

African (AFR) AF: 0.0748 AC: 2504 AN: 33476

American (AMR) AF: 0.247 AC: 11039 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 5410 AN: 26130

East Asian (EAS) AF: 0.296 AC: 11754 AN: 39700

South Asian (SAS) AF: 0.252 AC: 21709 AN: 86250

European-Finnish (FIN) AF: 0.272 AC: 14549 AN: 53406

Middle Eastern (MID) AF: 0.216 AC: 1246 AN: 5762

European-Non Finnish (NFE) AF: 0.227 AC: 252864 AN: 1111714

Other (OTH) AF: 0.229 AC: 13825 AN: 60384

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

African (AFR) AF: 0.0783 AC: 3252 AN: 41554

American (AMR) AF: 0.232 AC: 3543 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 735 AN: 3470

East Asian (EAS) AF: 0.304 AC: 1576 AN: 5182

South Asian (SAS) AF: 0.252 AC: 1213 AN: 4818

European-Finnish (FIN) AF: 0.261 AC: 2763 AN: 10602

Middle Eastern (MID) AF: 0.166 AC: 48 AN: 290

European-Non Finnish (NFE) AF: 0.231 AC: 15739 AN: 68008

Other (OTH) AF: 0.212 AC: 448 AN: 2116

Alfa AF: 0.207 Hom.: 1567

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

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 14, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

Usher syndrome type 3B Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.93
DANN	Benign	0.59
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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