chr5-140674297-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002109.6(HARS1):ā€‹c.1490A>Cā€‹(p.Glu497Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

HARS1
NM_002109.6 missense

Scores

3
10
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.77
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HARS1NM_002109.6 linkuse as main transcriptc.1490A>C p.Glu497Ala missense_variant 13/13 ENST00000504156.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HARS1ENST00000504156.7 linkuse as main transcriptc.1490A>C p.Glu497Ala missense_variant 13/131 NM_002109.6 P3P12081-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
29
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152124
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Usher syndrome type 3B Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 05, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HARS protein function. ClinVar contains an entry for this variant (Variation ID: 1680282). This variant has not been reported in the literature in individuals affected with HARS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 497 of the HARS protein (p.Glu497Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
.;T;T;T;T;.;.;T
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;.;D;D;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.72
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
2.0
.;.;M;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-4.8
D;D;.;D;D;D;D;D
REVEL
Pathogenic
0.70
Sift
Benign
0.036
D;D;.;T;T;D;T;T
Sift4G
Benign
0.24
T;T;.;T;T;T;T;T
Polyphen
1.0, 1.0
.;D;D;D;.;.;.;D
Vest4
0.67
MutPred
0.57
.;.;Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);.;.;.;.;
MVP
0.93
MPC
1.3
ClinPred
0.99
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.66
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1758219575; hg19: chr5-140053882; API