rs1553657387

Positions:

• chr2-203870636-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_005214.5(CTLA4):​c.160G>A​(p.Ala54Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A54P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.60

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a chain Cytotoxic T-lymphocyte protein 4 (size 187) in uniprot entity CTLA4_HUMAN there are 18 pathogenic changes around while only 1 benign (95%) in NM_005214.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-203870636-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 2128011.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP5: Variant 2-203870636-G-A is Pathogenic according to our data. Variant chr2-203870636-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 430905.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTLA4	NM_005214.5	c.160G>A	p.Ala54Thr	missense_variant	2/4	ENST00000648405.2
CTLA4	NM_001037631.3	c.160G>A	p.Ala54Thr	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTLA4	ENST00000648405.2	c.160G>A	p.Ala54Thr	missense_variant	2/4		NM_005214.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 54 of the CTLA4 protein (p.Ala54Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CTLA4 haploinsufficiency (PMID: 28983403, 29077208, 34628649, 35599849). ClinVar contains an entry for this variant (Variation ID: 430905). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Immunology, University Hospital Southampton NHSFT	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T;T;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D;D;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.62	D;D;D;D
MetaSVM	Uncertain	0.18	D
MutationAssessor	Uncertain	2.7	M;M;M;M
MutationTaster	Benign	0.86	D;D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	.;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	.;D;D;D
Sift4G	Uncertain	0.010	.;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.71, 0.77, 0.84
MutPred		0.55		Gain of phosphorylation at A54 (P = 0.0618);Gain of phosphorylation at A54 (P = 0.0618);Gain of phosphorylation at A54 (P = 0.0618);Gain of phosphorylation at A54 (P = 0.0618);
MVP		0.77
MPC		1.7
ClinPred		0.97	D
GERP RS		4.2
Varity_R		0.72
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553657387; hg19: chr2-204735359;