rs140540222
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
Consequence
NM_012208.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000789 AC: 12AN: 152106Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251496Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135922
GnomAD4 exome AF: 0.0000800 AC: 117AN: 1461860Hom.: 0 Cov.: 33 AF XY: 0.0000770 AC XY: 56AN XY: 727230
GnomAD4 genome AF: 0.0000789 AC: 12AN: 152106Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74298
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
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) -
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. -
Perrault syndrome 2 Pathogenic:1
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at