rs770117143
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000553.6(WRN):c.3309G>A(p.Lys1103=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,597,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Consequence
NM_000553.6 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.3309G>A | p.Lys1103= | splice_region_variant, synonymous_variant | 27/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.3309G>A | p.Lys1103= | splice_region_variant, synonymous_variant | 27/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.1942G>A | splice_region_variant, non_coding_transcript_exon_variant | 15/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*2923G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 26/34 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445864Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 718492
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74216
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 02, 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1064037). This variant has been observed in individual(s) with clinical features of Werner syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 1103 of the WRN mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the WRN protein. This variant also falls at the last nucleotide of exon 27, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at