rs778725551
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_152383.5(DIS3L2):c.2585C>T(p.Thr862Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,609,620 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 (★). Synonymous variant affecting the same amino acid position (i.e. T862T) has been classified as Likely benign.
Frequency
Consequence
NM_152383.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIS3L2 | NM_152383.5 | c.2585C>T | p.Thr862Ile | missense_variant | 21/21 | ENST00000325385.12 | |
DIS3L2 | NM_001257281.2 | c.1582-6788C>T | intron_variant | ||||
DIS3L2 | NR_046476.2 | n.2658C>T | non_coding_transcript_exon_variant | 21/21 | |||
DIS3L2 | NR_046477.2 | n.3231C>T | non_coding_transcript_exon_variant | 19/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIS3L2 | ENST00000325385.12 | c.2585C>T | p.Thr862Ile | missense_variant | 21/21 | 5 | NM_152383.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244416Hom.: 0 AF XY: 0.0000150 AC XY: 2AN XY: 133558
GnomAD4 exome AF: 0.00000343 AC: 5AN: 1457488Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725234
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152132Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74312
ClinVar
Submissions by phenotype
Perlman syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 862 of the DIS3L2 protein (p.Thr862Ile). This variant is present in population databases (rs778725551, gnomAD 0.007%). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 531942). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. - |
not provided Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The DIS3L2 p.T862I variant was not identified in the literature but was identified in dbSNP (ID: rs778725551) and ClinVar (classified as uncertain significance by Invitae for Renal hamartomas nephroblastomatosis and fetal gigantism). The variant was identified in control databases in 3 of 244416 chromosomes at a frequency of 0.00001227 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.T862 residue is conserved in mammals however computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at