rs762685242
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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):c.3582G>A(p.Thr1194Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,742 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). Synonymous variant affecting the same amino acid position (i.e. T1194T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
WRN
NM_000553.6 synonymous
NM_000553.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.87
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=-0.85).
BP6
Variant 8-31150350-G-A is Benign according to our data. Variant chr8-31150350-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 528201.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=-1.87 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| WRN | NM_000553.6 | c.3582G>A | p.Thr1194Thr | synonymous_variant | 31/35 | ENST00000298139.7 | NP_000544.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| WRN | ENST00000298139.7 | c.3582G>A | p.Thr1194Thr | synonymous_variant | 31/35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
| WRN | ENST00000521620.5 | n.2215G>A | non_coding_transcript_exon_variant | 19/23 | 1 | |||||
| WRN | ENST00000650667.1 | n.*3196G>A | non_coding_transcript_exon_variant | 30/34 | ENSP00000498593.1 | |||||
| WRN | ENST00000650667.1 | n.*3196G>A | 3_prime_UTR_variant | 30/34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000597 AC: 15AN: 251342Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135844
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461698Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727142
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GnomAD4 genome 0.0000592 AC: 9AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74256
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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
Werner syndrome Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
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DANN
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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