Genetic Variant CTLA4:c.109+76A>T (chr2-203868127-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005214.5(CTLA4):c.109+76A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000973 in 1,027,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.7e-7 ( 0 hom. )

Consequence

CTLA4
NM_005214.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.22

Publications

6 publications found

Variant links:

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

CTLA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.24).

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.109+76A>T		intron	N/A	NP_005205.2
	CTLA4	NM_001037631.3		c.109+76A>T		intron	N/A	NP_001032720.1	P16410-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CTLA4	ENST00000648405.2	MANE Select	c.109+76A>T	intron	N/A	ENSP00000497102.1	P16410-1
CTLA4	ENST00000487393.1	TSL:1	c.109+76A>T	intron	N/A	ENSP00000497319.1	P16410-3
CTLA4	ENST00000696479.1		c.181+76A>T	intron	N/A	ENSP00000512655.1	A0A8Q3SIR7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.73e-7

AC:

AN:

1027874

Hom.:

AF XY:

0.00000189

AC XY:

AN XY:

529014

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000401

AC:

AN:

24930

American (AMR)

AF:

0.00

AC:

AN:

41248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22854

East Asian (EAS)

AF:

0.00

AC:

AN:

37460

South Asian (SAS)

AF:

0.00

AC:

AN:

75844

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4944

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

722844

Other (OTH)

AF:

0.00

AC:

AN:

46388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

2.2

PromoterAI

-0.086

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over