rs140540222
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_012208.4(HARS2):c.448C>T(p.Arg150Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000799 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000080 ( 0 hom. )
Consequence
HARS2
NM_012208.4 missense
NM_012208.4 missense
Scores
10
6
2
Clinical Significance
Conservation
PhyloP100: 3.79
Genes affected
HARS2 (HGNC:4817): (histidyl-tRNA synthetase 2, mitochondrial) Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jul 2013]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.848
PP5
?
Variant 5-140695556-C-T is Pathogenic according to our data. Variant chr5-140695556-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214543.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=2}. Variant chr5-140695556-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.448C>T | p.Arg150Cys | missense_variant | 5/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.448C>T | p.Arg150Cys | missense_variant | 5/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152106Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251496Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135922
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GnomAD4 exome AF: 0.0000800 AC: 117AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727230
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GnomAD4 genome ? AF: 0.0000789 AC: 12AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74298
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 150 of the HARS2 protein (p.Arg150Cys). This variant is present in population databases (rs140540222, gnomAD 0.008%). This missense change has been observed in individuals with clinical features of Perrault syndrome (PMID: 31449985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 214543). 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 expected to disrupt HARS2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34406847, 31827252, 31449985) - |
Perrault syndrome 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 20, 2019 | Variant detected as compound heterozygous, together with c.172A>G in three siblings (two girls) with progressive sensorineural hearing impairment. Signs of premature ovarian failure were uncertain due to their young age. Variant detected as compound heterozygous, together with c.980G>A in a girl with progressive sensorineural hearing impairment. Signs of premature ovarian failure were uncertain due to her young age. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 01, 2016 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg150Cys variant in HARS2 has been reported by our laboratory in one individual with hea ring loss who was compound heterozygous for a second variant of uncertain signif icance in the HARS2 gene (this family). This variant has been identified in 6/1 21406 total chromosomes across all populations by the Exome Aggregation Consorti um (ExAC, http://exac.broadinstitute.org; dbSNP rs140540222). Although this vari ant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools suggest that the p.A rg150Cys variant may impact the protein, though this information is not predicti ve enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg150Cys variant is uncertain. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;D;.;.;.;.;D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;.;.;.;.;.;.;H;H;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;.;.;.;.;.;.;D
REVEL
Uncertain
Sift
Pathogenic
D;.;D;.;.;.;.;.;.;D
Sift4G
Pathogenic
D;.;.;.;.;.;.;.;.;D
Polyphen
D;.;.;.;.;.;.;D;D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
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