rs779902531
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_000553.6(WRN):āc.3801A>Gā(p.Gln1267=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000096 ( 0 hom. )
Consequence
WRN
NM_000553.6 synonymous
NM_000553.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.672
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 Likely_benign. Variant got -4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.55).
BP6
?
Variant 8-31154737-A-G is Benign according to our data. Variant chr8-31154737-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 458468.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
BP7
?
Synonymous conserved (PhyloP=-0.672 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.3801A>G | p.Gln1267= | synonymous_variant | 32/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.3801A>G | p.Gln1267= | synonymous_variant | 32/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.2434A>G | non_coding_transcript_exon_variant | 20/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*3415A>G | 3_prime_UTR_variant, NMD_transcript_variant | 31/34 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251296Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135816
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461218Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4AN XY: 726920
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74356
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
WRN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 24, 2022 | The WRN c.3801A>G variant is not predicted to result in an amino acid change (p.=). This variant is predicted to alter splicing based on available splicing prediction programs (Alamut Visual v2.11). However, the use of computer prediction programs is not equivalent to functional evidence. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-31012253-A-G) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/458468/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Werner syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at