rs191608083
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_152383.5(DIS3L2):c.1722G>T(p.Glu574Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E574A) 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_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIS3L2 | NM_152383.5 | c.1722G>T | p.Glu574Asp | missense_variant | 14/21 | ENST00000325385.12 | |
DIS3L2 | NM_001257281.2 | c.1581+36740G>T | intron_variant | ||||
DIS3L2 | NR_046476.2 | n.1868G>T | non_coding_transcript_exon_variant | 14/21 | |||
DIS3L2 | NR_046477.2 | n.1844G>T | non_coding_transcript_exon_variant | 13/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIS3L2 | ENST00000325385.12 | c.1722G>T | p.Glu574Asp | missense_variant | 14/21 | 5 | NM_152383.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000401 AC: 61AN: 152190Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000205 AC: 51AN: 249044Hom.: 0 AF XY: 0.000200 AC XY: 27AN XY: 135088
GnomAD4 exome AF: 0.000389 AC: 569AN: 1461464Hom.: 0 Cov.: 30 AF XY: 0.000402 AC XY: 292AN XY: 726986
GnomAD4 genome ? AF: 0.000401 AC: 61AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.000336 AC XY: 25AN XY: 74472
ClinVar
Submissions by phenotype
Perlman syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 13, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 19, 2021 | DNA sequence analysis of the DIS3L2 gene demonstrated a sequence change, c.1722G>T, in exon 14 that results in an amino acid change, p.Glu574Asp. This sequence change has been described in the gnomAD database with a frequency of 0.038% in the non-Finnish European subpopulation (dbSNP rs191608083). The p.Glu574Asp change affects a poorly conserved amino acid residue located in a domain of the DIS3L2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu574Asp substitution. This sequence change does not appear to have been previously described in individuals with DIS3L2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu574Asp change remains unknown at this time. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 19, 2021 | The c.1722G>T (p.E574D) alteration is located in exon 14 (coding exon 13) of the DIS3L2 gene. This alteration results from a G to T substitution at nucleotide position 1722, causing the glutamic acid (E) at amino acid position 574 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 21, 2022 | BP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at