rs541455377
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000553.6(WRN):āc.1145A>Gā(p.Lys382Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.1145A>G | p.Lys382Arg | missense_variant | 9/35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000651642.1 | c.440A>G | p.Lys147Arg | missense_variant | 3/4 | ENSP00000498779.1 | ||||
WRN | ENST00000650667.1 | n.*759A>G | non_coding_transcript_exon_variant | 8/34 | ENSP00000498593.1 | |||||
WRN | ENST00000650667 | n.*759A>G | 3_prime_UTR_variant | 8/33 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152238Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250570Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135442
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461748Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727172
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152356Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74502
ClinVar
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 18, 2022 | The c.1145A>G (p.K382R) 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 1145, causing the lysine (K) at amino acid position 382 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2022 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 382 of the WRN protein (p.Lys382Arg). This variant is present in population databases (rs541455377, gnomAD 0.02%). 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: 574239). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine 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. - |
Ovarian cancer Benign:1
Benign, criteria provided, single submitter | clinical testing | Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Jan 01, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at