5-140674735-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002109.6(HARS1):c.1402G>A(p.Glu468Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00014 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
HARS1
NM_002109.6 missense
NM_002109.6 missense
Scores
1
13
3
Clinical Significance
Conservation
PhyloP100: 6.08
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 |
---|---|---|---|---|---|---|---|
HARS1 | NM_002109.6 | c.1402G>A | p.Glu468Lys | missense_variant | 12/13 | ENST00000504156.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS1 | ENST00000504156.7 | c.1402G>A | p.Glu468Lys | missense_variant | 12/13 | 1 | NM_002109.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 152204Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000103 AC: 26AN: 251428Hom.: 0 AF XY: 0.0000883 AC XY: 12AN XY: 135886
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GnomAD4 exome AF: 0.000140 AC: 205AN: 1461874Hom.: 0 Cov.: 34 AF XY: 0.000135 AC XY: 98AN XY: 727242
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GnomAD4 genome ? AF: 0.000138 AC: 21AN: 152322Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10AN XY: 74480
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 01, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Usher syndrome type 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 468 of the HARS protein (p.Glu468Lys). This variant is present in population databases (rs199615869, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 540202). 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 with a negative predictive value of 80%. In 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 01, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;.;T;T;D;T;T
Sift4G
Benign
T;T;.;T;T;T;T;T
Polyphen
0.61, 0.56, 0.76
.;P;P;P;.;.;.;P
Vest4
MVP
MPC
1.2
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at