rs606231417
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_005214.5(CTLA4):c.151C>T(p.Arg51Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
CTLA4
NM_005214.5 stop_gained
NM_005214.5 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 1.30
Genes affected
CTLA4 (HGNC:2505): (cytotoxic T-lymphocyte associated protein 4) This gene is a member of the immunoglobulin superfamily and encodes a protein which transmits an inhibitory signal to T cells. The protein contains a V domain, a transmembrane domain, and a cytoplasmic tail. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. The membrane-bound isoform functions as a homodimer interconnected by a disulfide bond, while the soluble isoform functions as a monomer. Mutations in this gene have been associated with insulin-dependent diabetes mellitus, Graves disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, thyroid-associated orbitopathy, and other autoimmune diseases. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-203870627-C-T is Pathogenic according to our data. Variant chr2-203870627-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 161109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CTLA4 | NM_005214.5 | c.151C>T | p.Arg51Ter | stop_gained | 2/4 | ENST00000648405.2 | |
CTLA4 | NM_001037631.3 | c.151C>T | p.Arg51Ter | stop_gained | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CTLA4 | ENST00000648405.2 | c.151C>T | p.Arg51Ter | stop_gained | 2/4 | NM_005214.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Arg51*) in the CTLA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CTLA4 are known to be pathogenic (PMID: 25213377, 25329329). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CTLA4 deficiency (PMID: 25213377). ClinVar contains an entry for this variant (Variation ID: 161109). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 26, 2014 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2020 | The alteration results in a premature stop codon: _x000D_ _x000D_ The c.151C>T (p.R51*) alteration, located in coding exon 2 of the CTLA4 gene, results from a C to T substitution at nucleotide position 151. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 51. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported in multiple patients with immune related symptoms (Kuehn, 2014; Besnard, 2018; Buchbinder, 2018; Schwab, 2018; Ayrignac, 2020). Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 17, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;D
Vest4
0.83, 0.87, 0.92
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at