rs751260098
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001905.4(CTPS1):āc.221A>Gā(p.Tyr74Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000025 in 1,602,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Synonymous variant affecting the same amino acid position (i.e. Y74Y) has been classified as Likely benign.
Frequency
Consequence
NM_001905.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTPS1 | NM_001905.4 | c.221A>G | p.Tyr74Cys | missense_variant | 3/19 | ENST00000650070.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTPS1 | ENST00000650070.2 | c.221A>G | p.Tyr74Cys | missense_variant | 3/19 | NM_001905.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000808 AC: 2AN: 247388Hom.: 0 AF XY: 0.0000149 AC XY: 2AN XY: 133796
GnomAD4 exome AF: 0.00000207 AC: 3AN: 1450470Hom.: 0 Cov.: 30 AF XY: 0.00000278 AC XY: 2AN XY: 720464
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
Severe combined immunodeficiency due to CTPS1 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 16, 2020 | This variant has not been reported in the literature in individuals with CTPS1-related disease. This variant is present in population databases (rs751260098, ExAC 0.003%). This sequence change replaces tyrosine with cysteine at codon 74 of the CTPS1 protein (p.Tyr74Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at