rs746478253
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5
The NM_015836.4(WARS2):βc.797delCβ(p.Pro266ArgfsTer10) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,614,130 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P266P) has been classified as Likely benign.
Frequency
Consequence
NM_015836.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WARS2 | ENST00000235521.5 | c.797delC | p.Pro266ArgfsTer10 | frameshift_variant | Exon 6 of 6 | 1 | NM_015836.4 | ENSP00000235521.4 | ||
WARS2 | ENST00000369426 | c.*163delC | 3_prime_UTR_variant | Exon 6 of 6 | 1 | ENSP00000358434.5 | ||||
WARS2 | ENST00000495746.5 | n.*100delC | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152258Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000359 AC: 9AN: 250918Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135680
GnomAD4 exome AF: 0.0000246 AC: 36AN: 1461872Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 727238
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152258Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74398
ClinVar
Submissions by phenotype
Neurodevelopmental disorder, mitochondrial, with abnormal movements and lactic acidosis, with or without seizures Pathogenic:2Uncertain:1
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not provided Pathogenic:2
DNA sequence analysis of the WARS2 gene demonstrated a one base pair deletion in exon 6, c.797del. This deletion is predicted to result in a frameshift and creation of a premature stop codon nine amino acids downstream, p.Pro266Argfs*10. The c.797del has been described at a low population frequency of 0.004% in gnomAD. The second sequence change identified, c.938A>T, occurs in exon 6 and results in an amino acid change, p.Lys313Met. The p.Lys313Met change affects a moderately conserved amino acid residue located in a domain of the WARS2 protein that is known to be functional. This sequence change has been described in the gnomAD database with a low population frequency of 0.02% (dbSNP rs145867327). The c.797del and c.938A>T sequence changes have been reported in the trans state (on different chromosomes) in two affected siblings with WARS2-related phenotypes (Wortmann et al., 2017. Hum Mutat 38: 1786-1795). -
Frameshift variant predicted to result in protein truncation as the last 95 amino acids are replaced with 9 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 6447871, 17604309, 24639874, 28236339, 28905505, 28650581, 25385316, 25361775, 25130867, 27389904, 10828066, 15779907, 12557294, 2999114, 7219534, 6997870, 6932013, 31628766, 31617452, 31684799, 31282308, 29783990) -
Parkinsonism-dystonia 3, childhood-onset Pathogenic:1
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Inborn genetic diseases Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at