rs58302597

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

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 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: G2P, Labcorp Genetics (formerly Invitae)
Usher syndrome type 3
Inheritance: AR Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen

HARS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	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	P12081-4
HARS1	NM_001289094.2		c.1371+7G>A	splice_region intron	N/A	NP_001276023.1

Ensembl Transcripts

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	P12081-1
HARS1	ENST00000457527.6	TSL:1	c.1398+7G>A		splice_region intron	N/A	ENSP00000387893.2	P12081-4
HARS1	ENST00000675204.1		c.1465G>A	p.Glu489Lys	missense	Exon 12 of 12	ENSP00000501643.1	A0A6Q8PF47

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29334

AN:

152124

Hom.:

3327

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.231

AC XY:

167614

AN XY:

727096

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

14084

28168

42253

56337

70421

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8616

17232

25848

34464

43080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.193

AC:

29359

AN:

152242

Hom.:

3343

Cov.:

AF XY:

0.194

AC XY:

14473

AN XY:

74426

show subpopulations

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:

AN:

290

European-Non Finnish (NFE)

AF:

0.231

AC:

15739

AN:

68008

Other (OTH)

AF:

0.212

AC:

448

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1199

2399

3598

4798

5997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

306

612

918

1224

1530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Usher syndrome type 3B (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.93

(source)

DANN

Benign

0.59

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over