rs1553657430

Variant names:

• chr2-203870888-C-A
• rs1553657430
• NM_005214.5:c.412C>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_005214.5(CTLA4):​c.412C>A​(p.Pro138Thr) variant causes a missense change. 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 (★). ClinVar reports functional evidence for this variant: "SCV001589652: Experimental studies have shown that this missense change affects CTLA4 function (PMID:26478010).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P138S) has been classified as Likely pathogenic. The gene CTLA4 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.24
• Publications: 2 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: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Specifications for CTLA4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001589652: Experimental studies have shown that this missense change affects CTLA4 function (PMID: 26478010).
• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 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 chr2-203870888-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3906997.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 2-203870888-C-A is Pathogenic according to our data. Variant chr2-203870888-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 495051.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005214.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	NM_005214.5	MANE Select	c.412C>A	p.Pro138Thr	missense	Exon 2 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.412C>A	p.Pro138Thr	missense	Exon 2 of 3	NP_001032720.1	P16410-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTLA4	ENST00000648405.2	MANE Select	c.412C>A	p.Pro138Thr	missense	Exon 2 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000487393.1	TSL:1	c.110-1820C>A		intron	N/A	ENSP00000497319.1	P16410-3
	CTLA4	ENST00000696479.1		c.484C>A	p.Pro162Thr	missense	Exon 3 of 5	ENSP00000512655.1	A0A8Q3SIR7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsufficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.060	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		5.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.72		Loss of glycosylation at P137 (P = 0.0555)
MVP		0.63
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.91
gMVP		0.90
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1553657430; hg19: chr2-204735611;