rs750246326
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000553.6(WRN):c.1304C>T(p.Ser435Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,611,022 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S435S) has been classified as Likely benign.
Frequency
Consequence
NM_000553.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.1304C>T | p.Ser435Phe | missense_variant | 10/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.1304C>T | p.Ser435Phe | missense_variant | 10/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000651642.1 | c.565-1433C>T | intron_variant | ||||||
WRN | ENST00000650667.1 | c.*918C>T | 3_prime_UTR_variant, NMD_transcript_variant | 9/34 |
Frequencies
GnomAD3 genomes ? AF: 0.0000264 AC: 4AN: 151522Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250828Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135676
GnomAD4 exome AF: 0.0000110 AC: 16AN: 1459500Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10AN XY: 726242
GnomAD4 genome ? AF: 0.0000264 AC: 4AN: 151522Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 73982
ClinVar
Submissions by phenotype
Werner syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 571849). This variant has not been reported in the literature in individuals affected with WRN-related conditions. This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 435 of the WRN protein (p.Ser435Phe). This variant is present in population databases (rs750246326, gnomAD 0.004%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at