Genetic Variant HARS1:p.Cys196Trp (chr5-140677950-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002109.6(HARS1):c.588C>G(p.Cys196Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,774 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. C196C) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HARS1
NM_002109.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.857

Publications

0 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

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HARS1	NM_002109.6 link	c.588C>G	p.Cys196Trp	missense_variant	Exon 6 of 13	ENST00000504156.7	NP_002100.2	P12081-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HARS1	ENST00000504156.7 link	c.588C>G	p.Cys196Trp	missense_variant	Exon 6 of 13	1	NM_002109.6	ENSP00000425634.1		P12081-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459774

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726368

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1110094

Other (OTH)

AF:

0.0000166

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

.;T;T;T;T;.;.;T

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

D;D;.;D;D;D;D;D

M_CAP

Benign

0.044

MetaRNN

Uncertain

0.49

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Benign

1.7

.;.;L;L;.;.;.;.

PhyloP100

0.86

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.0

D;D;.;D;D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.024

D;D;.;D;D;D;D;D

Sift4G

Benign

0.14

T;T;.;T;T;T;T;T

Polyphen

0.12, 0.98, 0.45

.;B;D;D;.;.;.;B

Vest4

0.57

MutPred

0.52

.;.;Loss of catalytic residue at I194 (P = 0.0931);Loss of catalytic residue at I194 (P = 0.0931);.;.;.;.;

MVP

0.68

MPC

1.3

ClinPred

0.91

GERP RS

0.30

Varity_R

0.82

gMVP

0.91

Mutation Taster

=49/51

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over