rs767352102

chr2-203867946-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005214.5(CTLA4):c.4G>T(p.Ala2Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CTLA4 NM_005214.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22379369).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000592 (9/152146) while in subpopulation AMR AF= 0.000393 (6/15278). AF 95% confidence interval is 0.00017. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTLA4	NM_005214.5	c.4G>T	p.Ala2Ser	missense_variant	1/4	ENST00000648405.2
CTLA4	NM_001037631.3	c.4G>T	p.Ala2Ser	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTLA4	ENST00000648405.2	c.4G>T	p.Ala2Ser	missense_variant	1/4		NM_005214.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251344 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461464 Hom.: 0 Cov.: 29 AF XY: 0.00000963 AC XY: 7 AN XY: 727070

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autoimmune lymphoproliferative syndrome due to CTLA4 haploinsuffiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2 of the CTLA4 protein (p.Ala2Ser). This variant is present in population databases (rs767352102, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CTLA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 542072). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T;.;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.34	T
Polyphen		0.83	P;P;.;.;P
Vest4		0.083, 0.15, 0.16
MutPred		0.46		Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);Gain of disorder (P = 0.0401);
MVP		0.53
MPC		1.2
ClinPred		0.61	D
GERP RS		3.0
Varity_R		0.088
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs767352102; hg19: chr2-204732669;