rs774682373
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_002109.6(HARS1):c.1123C>T(p.Arg375Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000322 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R375H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
HARS1
NM_002109.6 missense
NM_002109.6 missense
Scores
2
11
4
Clinical Significance
Conservation
PhyloP100: 3.95
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.1123C>T | p.Arg375Cys | missense_variant | 10/13 | ENST00000504156.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS1 | ENST00000504156.7 | c.1123C>T | p.Arg375Cys | missense_variant | 10/13 | 1 | NM_002109.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251468Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135904
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GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000385 AC XY: 28AN XY: 727240
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 20, 2023 | The c.1123C>T (p.R375C) alteration is located in exon 10 (coding exon 10) of the HARS gene. This alteration results from a C to T substitution at nucleotide position 1123, causing the arginine (R) at amino acid position 375 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 01, 2022 | 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 | Jul 21, 2023 | 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. 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: 472986). This variant has not been reported in the literature in individuals affected with HARS-related conditions. This variant is present in population databases (rs774682373, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 375 of the HARS protein (p.Arg375Cys). - |
Usher syndrome type 3;C3281066:Usher syndrome type 3B;C5567486:Autosomal dominant Charcot-Marie-Tooth disease type 2W Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 05-04-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
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;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;.;D;D;D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;D;D;D;D
Sift4G
Uncertain
D;T;.;T;T;D;T;T;.
Polyphen
0.070, 0.043, 0.042
.;B;B;B;.;.;.;B;.
Vest4
MutPred
0.55
.;.;Gain of catalytic residue at V377 (P = 0.0598);Gain of catalytic residue at V377 (P = 0.0598);.;.;.;.;.;
MVP
MPC
0.59
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at