chr5-140693607-T-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_012208.4(HARS2):āc.125T>Gā(p.Leu42Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,613,920 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). Synonymous variant affecting the same amino acid position (i.e. L42L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_012208.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HARS2 | NM_012208.4 | c.125T>G | p.Leu42Ter | stop_gained | 2/13 | ENST00000230771.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HARS2 | ENST00000230771.9 | c.125T>G | p.Leu42Ter | stop_gained | 2/13 | 1 | NM_012208.4 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152170Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251488Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135918
GnomAD4 exome AF: 0.000109 AC: 159AN: 1461750Hom.: 0 Cov.: 32 AF XY: 0.000100 AC XY: 73AN XY: 727182
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74330
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2022 | This sequence change creates a premature translational stop signal (p.Leu42*) in the HARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HARS2 are known to be pathogenic (PMID: 31827252). This variant is present in population databases (rs146046742, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with HARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1176814). For these reasons, this variant has been classified as Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | HARS2: PM2:Supporting - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at