8-31150354-GA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000553.6(WRN):βc.3590delβ(p.Asn1197ThrfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. E1196E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000553.6 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
WRN | NM_000553.6 | c.3590del | p.Asn1197ThrfsTer2 | frameshift_variant | 31/35 | ENST00000298139.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
WRN | ENST00000298139.7 | c.3590del | p.Asn1197ThrfsTer2 | frameshift_variant | 31/35 | 1 | NM_000553.6 | P1 | |
WRN | ENST00000521620.5 | n.2223del | non_coding_transcript_exon_variant | 19/23 | 1 | ||||
WRN | ENST00000650667.1 | c.*3204del | 3_prime_UTR_variant, NMD_transcript_variant | 30/34 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461798Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727192
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152170Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74340
ClinVar
Submissions by phenotype
Werner syndrome Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2023 | This sequence change creates a premature translational stop signal (p.Asn1197Thrfs*2) in the WRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in WRN are known to be pathogenic (PMID: 16673358). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Werner syndrome (PMID: 16673358, 20443122). This variant is also known as 3587delA. ClinVar contains an entry for this variant (Variation ID: 38890). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 13, 2022 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Potential founder variant in the Dutch population. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 31, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at