chr8-31080874-A-G
Variant summary
Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000553.6(WRN):c.847A>G(p.Ile283Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,604,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. I283L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
Publications
- Werner syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
- osteosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
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ACMG classification
Our verdict: Likely_benign. The variant received -2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.847A>G | p.Ile283Val | missense_variant | Exon 9 of 35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000651642.1 | c.142A>G | p.Ile48Val | missense_variant | Exon 3 of 4 | ENSP00000498779.1 | ||||
WRN | ENST00000650667.1 | n.*461A>G | non_coding_transcript_exon_variant | Exon 8 of 34 | ENSP00000498593.1 | |||||
WRN | ENST00000650667.1 | n.*461A>G | 3_prime_UTR_variant | Exon 8 of 34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152092Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000249 AC: 6AN: 240922 AF XY: 0.0000459 show subpopulations
GnomAD4 exome AF: 0.0000399 AC: 58AN: 1452114Hom.: 0 Cov.: 31 AF XY: 0.0000388 AC XY: 28AN XY: 722094 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152092Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74300 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
The c.847A>G (p.I283V) alteration is located in exon 9 (coding exon 8) of the WRN gene. This alteration results from a A to G substitution at nucleotide position 847, causing the isoleucine (I) at amino acid position 283 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Werner syndrome Uncertain:1
This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 283 of the WRN protein (p.Ile283Val). This variant is present in population databases (rs201643901, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with WRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 528182). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at