rs878854138
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000553.6(WRN):c.3209_3211delinsTTT(p.Cys1070_Pro1071delinsPheSer) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
WRN
NM_000553.6 missense
NM_000553.6 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.42
Genes affected
WRN (HGNC:12791): (WRN RecQ like helicase) This gene encodes a member of the RecQ subfamily of DNA helicase proteins. The encoded nuclear protein is important in the maintenance of genome stability and plays a role in DNA repair, replication, transcription and telomere maintenance. This protein contains a N-terminal 3' to 5' exonuclease domain, an ATP-dependent helicase domain and RQC (RecQ helicase conserved region) domain in its central region, and a C-terminal HRDC (helicase RNase D C-terminal) domain and nuclear localization signal. Defects in this gene are the cause of Werner syndrome, an autosomal recessive disorder characterized by accelerated aging and an elevated risk for certain cancers. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.3209_3211delinsTTT | p.Cys1070_Pro1071delinsPheSer | missense_variant | 26/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.3209_3211delinsTTT | p.Cys1070_Pro1071delinsPheSer | missense_variant | 26/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.1842_1844delinsTTT | non_coding_transcript_exon_variant | 14/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*2823_*2825delinsTTT | 3_prime_UTR_variant, NMD_transcript_variant | 25/34 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Werner syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2017 | This variant, c.3209_3211delinsTTT, is a complex sequence change that replaces two amino acids, cysteine and proline with phenyalanine and serine at codons 1070-1071 of the WRN protein (p.Cys1070_Pro1071delinsPheSer). The cysteine and proline residues are moderately conserved. This variant is reported as two separate single-nucleotide changes in population databases (c.3209G>T, ExAC 0.1% and c.3211C>T, ExAC 0.1%). However, in the read data for all individuals displayed in the ExAC browser, these two variants are in cis. This recapitulates the variant observed here (c.3209_3211delinsTTT) and indicates that this variant is very likely present in the population databases at 0.1%. This variant has not been reported in the literature in individuals with WRN-related disease. ClinVar contains an entry for this variant (Variation ID: 238148). While algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that the two missense changes, p.Cys1070Phe and p.Pro1071Ser are likely to be tolerated independently, it is uncertain how these two amino acid changes in combination affect protein function. 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 | Fulgent Genetics, Fulgent Genetics | May 25, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at