rs281865548
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5
The NM_001143992.2(WRAP53):c.1192C>T(p.Arg398Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,613,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R398Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_001143992.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRAP53 | NM_001143992.2 | c.1192C>T | p.Arg398Trp | missense_variant | 9/11 | ENST00000396463.7 | |
WRAP53 | NM_001143990.2 | c.1192C>T | p.Arg398Trp | missense_variant | 9/11 | ||
WRAP53 | NM_001143991.2 | c.1192C>T | p.Arg398Trp | missense_variant | 9/11 | ||
WRAP53 | NM_018081.2 | c.1192C>T | p.Arg398Trp | missense_variant | 8/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRAP53 | ENST00000396463.7 | c.1192C>T | p.Arg398Trp | missense_variant | 9/11 | 1 | NM_001143992.2 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152132Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000223 AC: 56AN: 251090Hom.: 0 AF XY: 0.000192 AC XY: 26AN XY: 135710
GnomAD4 exome AF: 0.000146 AC: 214AN: 1461598Hom.: 0 Cov.: 33 AF XY: 0.000150 AC XY: 109AN XY: 727104
GnomAD4 genome AF: 0.000164 AC: 25AN: 152132Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7AN XY: 74328
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 398 of the WRAP53 protein (p.Arg398Trp). This variant is present in population databases (rs281865548, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of Hoyeraal Hreidarsson syndrome or dyskeratosis congenita (PMID: 21205863, 32303682). ClinVar contains an entry for this variant (Variation ID: 30975). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects WRAP53 function (PMID: 21205863, 32303682). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 29, 2015 | - - |
Dyskeratosis congenita, autosomal recessive 3 Pathogenic:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2011 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Hauer Lab, Department Of Pediatric Oncology, Technical University Munich | - | ACMG/AMP, PVS1, PM2 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at