rs577000913
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000553.6(WRN):āc.1840A>Gā(p.Ile614Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,248 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 (ā ā ).
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.1840A>G | p.Ile614Val | missense_variant | 16/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.1840A>G | p.Ile614Val | missense_variant | 16/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.473A>G | non_coding_transcript_exon_variant | 4/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*1454A>G | 3_prime_UTR_variant, NMD_transcript_variant | 15/34 |
Frequencies
GnomAD3 genomes ? AF: 0.0000789 AC: 12AN: 152160Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251176Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135730
GnomAD4 exome AF: 0.0000445 AC: 65AN: 1460970Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29AN XY: 726804
GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152278Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74464
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 03, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 28, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 614 of the WRN protein (p.Ile614Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 404036). 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 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. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2022 | The c.1840A>G (p.I614V) alteration is located in exon 16 (coding exon 15) of the WRN gene. This alteration results from a A to G substitution at nucleotide position 1840, causing the isoleucine (I) at amino acid position 614 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at