rs767325912
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_002109.6(HARS1):c.218G>A(p.Arg73His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,698 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73C) has been classified as Uncertain significance.
Frequency
Consequence
NM_002109.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS1 | NM_002109.6 | c.218G>A | p.Arg73His | missense_variant | 3/13 | ENST00000504156.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS1 | ENST00000504156.7 | c.218G>A | p.Arg73His | missense_variant | 3/13 | 1 | NM_002109.6 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251480Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135912
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461496Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 727080
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74360
ClinVar
Submissions by phenotype
Usher syndrome type 3B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 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 expected to disrupt HARS protein function. ClinVar contains an entry for this variant (Variation ID: 578146). This variant has not been reported in the literature in individuals affected with HARS-related conditions. This variant is present in population databases (rs767325912, gnomAD 0.007%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 73 of the HARS protein (p.Arg73His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at