rs1553657387

Variant names:

• chr2-203870636-G-A
• rs1553657387
• NM_005214.5:c.160G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-203870636-G-A
• chr2-203870636-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 1 publications found

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]

CTLA4 Gene-Disease associations (from GenCC):

• autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain 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 VariationId 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 VariationId is 430905.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.160G>A	p.Ala54Thr	missense_variant	Exon 2 of 4		NM_005214.5	ENSP00000497102.1

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

Jan 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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Department of Immunology, University Hospital Southampton NHSFT

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		6.6
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
Mutation Taster		=19/81	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553657387; hg19: chr2-204735359;