dbSNP rs2230361: HARS1:p.Cys196Cys (chr5-140677950-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -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:4

Conservation

PhyloP100: 0.857

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

HARS1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002109.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 226651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

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	HGVSp	Effect	Exon Rank	Protein	UniProt
HARS1	NM_002109.6	MANE Select	c.588C>T	p.Cys196Cys	synonymous	Exon 6 of 13	NP_002100.2
HARS1	NM_001258041.3		c.528C>T	p.Cys176Cys	synonymous	Exon 6 of 13	NP_001244970.1	P12081-4
HARS1	NM_001289094.2		c.501C>T	p.Cys167Cys	synonymous	Exon 6 of 13	NP_001276023.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HARS1	ENST00000504156.7	TSL:1 MANE Select	c.588C>T	p.Cys196Cys	synonymous	Exon 6 of 13	ENSP00000425634.1	P12081-1
HARS1	ENST00000457527.6	TSL:1	c.528C>T	p.Cys176Cys	synonymous	Exon 6 of 13	ENSP00000387893.2	P12081-4
HARS1	ENST00000942727.1		c.705C>T	p.Cys235Cys	synonymous	Exon 7 of 14	ENSP00000612786.1

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

GnomAD2 exomes

AF:

0.0796

AC:

20016

AN:

251300

AF XY:

0.0804

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 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

African (AFR)

AF:

0.0590

AC:

1973

AN:

33414

American (AMR)

AF:

0.123

AC:

5499

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0316

AC:

826

AN:

26122

East Asian (EAS)

AF:

0.000806

AC:

AN:

39686

South Asian (SAS)

AF:

0.106

AC:

9119

AN:

86170

European-Finnish (FIN)

AF:

0.0868

AC:

4638

AN:

53416

Middle Eastern (MID)

AF:

0.0543

AC:

313

AN:

5760

European-Non Finnish (NFE)

AF:

0.0781

AC:

86617

AN:

1109064

Other (OTH)

AF:

0.0689

AC:

4155

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

4877

9754

14631

19508

24385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3168

6336

9504

12672

15840

<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:

0.0743

AC:

11264

AN:

151658

Hom.:

488

Cov.:

AF XY:

0.0760

AC XY:

5625

AN XY:

74058

show subpopulations

African (AFR)

AF:

0.0644

AC:

2661

AN:

41294

American (AMR)

AF:

0.0896

AC:

1361

AN:

15198

Ashkenazi Jewish (ASJ)

AF:

0.0367

AC:

127

AN:

3462

East Asian (EAS)

AF:

0.00271

AC:

AN:

5168

South Asian (SAS)

AF:

0.0945

AC:

452

AN:

4784

European-Finnish (FIN)

AF:

0.0791

AC:

832

AN:

10520

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0805

AC:

5468

AN:

67924

Other (OTH)

AF:

0.0684

AC:

144

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

482

965

1447

1930

2412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0743

Hom.:

461

Bravo

AF:

0.0733

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.0725

EpiControl

AF:

0.0710

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 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.80

PhyloP100

0.86

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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