rs141563618
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000553.6(WRN):c.2114C>T(p.Thr705Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000243 in 1,614,036 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T705A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.2114C>T | p.Thr705Ile | missense_variant | 19/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2114C>T | p.Thr705Ile | missense_variant | 19/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.747C>T | non_coding_transcript_exon_variant | 7/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*1728C>T | 3_prime_UTR_variant, NMD_transcript_variant | 18/34 |
Frequencies
GnomAD3 genomes ? AF: 0.000184 AC: 28AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000358 AC: 90AN: 251388Hom.: 0 AF XY: 0.000339 AC XY: 46AN XY: 135868
GnomAD4 exome AF: 0.000249 AC: 364AN: 1461722Hom.: 0 Cov.: 31 AF XY: 0.000259 AC XY: 188AN XY: 727162
GnomAD4 genome ? AF: 0.000184 AC: 28AN: 152314Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74488
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 03, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 705 of the WRN protein (p.Thr705Ile). This variant is present in population databases (rs141563618, gnomAD 0.07%). This missense change has been observed in individual(s) with abnormal lipid metabolism and/or colorectal cancer (PMID: 26344056, 32041611). ClinVar contains an entry for this variant (Variation ID: 238135). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 05, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2022 | Variant summary: WRN c.2114C>T (p.Thr705Ile) results in a non-conservative amino acid change located in the DEAD/DEAH box helicase domain (IPR011545) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251388 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in WRN causing Werner Syndrome (0.00036 vs 0.0025), allowing no conclusion about variant significance. c.2114C>T has been reported in the literature as a non-informative genotype in an individual with familial colorectal carcinomas of an undefined genetic basis (example, Arora_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Werner Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect despite reporting an absence of helicase activity in-vitro (Arora_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at