rs766561388
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000553.6(WRN):c.2222G>A(p.Arg741Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,694 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 Uncertain significance (★★).
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.2222G>A | p.Arg741Gln | missense_variant | Exon 19 of 35 | 1 | NM_000553.6 | ENSP00000298139.5 | ||
WRN | ENST00000521620.5 | n.855G>A | non_coding_transcript_exon_variant | Exon 7 of 23 | 1 | |||||
WRN | ENST00000650667.1 | n.*1836G>A | non_coding_transcript_exon_variant | Exon 18 of 34 | ENSP00000498593.1 | |||||
WRN | ENST00000650667.1 | n.*1836G>A | 3_prime_UTR_variant | Exon 18 of 34 | ENSP00000498593.1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 151922Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251358Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135846
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1461772Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727182
GnomAD4 genome AF: 0.0000395 AC: 6AN: 151922Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74186
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 741 of the WRN protein (p.Arg741Gln). This variant is present in population databases (rs766561388, gnomAD 0.01%). 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: 576211). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamine 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. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at