rs757555204
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_152383.5(DIS3L2):c.1627C>T(p.Arg543Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R543H) has been classified as Uncertain significance.
Frequency
Consequence
NM_152383.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIS3L2 | NM_152383.5 | c.1627C>T | p.Arg543Cys | missense_variant | 13/21 | ENST00000325385.12 | |
DIS3L2 | NM_001257281.2 | c.1581+46C>T | intron_variant | ||||
DIS3L2 | NR_046476.2 | n.1773C>T | non_coding_transcript_exon_variant | 13/21 | |||
DIS3L2 | NR_046477.2 | n.1749C>T | non_coding_transcript_exon_variant | 12/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIS3L2 | ENST00000325385.12 | c.1627C>T | p.Arg543Cys | missense_variant | 13/21 | 5 | NM_152383.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249028Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135144
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461882Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6AN XY: 727240
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74338
ClinVar
Submissions by phenotype
Perlman syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2023 | This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This variant is present in population databases (rs757555204, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 543 of the DIS3L2 protein (p.Arg543Cys). ClinVar contains an entry for this variant (Variation ID: 572055). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DIS3L2 protein function. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at