8-31111747-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000553.6(WRN):c.2221C>T(p.Arg741*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,778 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000553.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2221C>T | p.Arg741* | stop_gained | Exon 19 of 35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000521620.5 | n.854C>T | non_coding_transcript_exon_variant | Exon 7 of 23 | 1 | |||||
WRN | ENST00000650667.1 | n.*1835C>T | non_coding_transcript_exon_variant | Exon 18 of 34 | ENSP00000498593.1 | |||||
WRN | ENST00000650667.1 | n.*1835C>T | 3_prime_UTR_variant | Exon 18 of 34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251368Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135848
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461778Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727190
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Werner syndrome Pathogenic:2
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This sequence change creates a premature translational stop signal (p.Arg741*) in the WRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). This variant is present in population databases (rs763089663, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with Werner syndrome (PMID: 20443122). ClinVar contains an entry for this variant (Variation ID: 528094). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at