2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*538_*571delATATATATATATATATATATATATATATATATAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_005214.5(CTLA4):​c.*538_*571delATATATATATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00635 in 183,254 control chromosomes in the GnomAD database, including 16 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene CTLA4 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0068 (9 hom., cov: 0)
  • Exomes 𝑓: 0.0054 (7 hom.)
• Consequence: CTLA4 NM_005214.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00685 (836/122104) while in subpopulation AMR AF = 0.0171 (210/12286). AF 95% confidence interval is 0.0152. There are 9 homozygotes in GnomAd4. There are 397 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 836 AD,Unknown gene.

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.*538_*571delATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*575_*608delATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 3 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.*538_*571delATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*538_*571delATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*549delATATATATATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.00684 AC: 835 AN: 122114 Hom.: 9 Cov.: 0

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.00565

Gnomad EAS AF: 0.000469

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.000861

Gnomad MID AF: 0.00397

Gnomad NFE AF: 0.00861

Gnomad OTH AF: 0.00755

GnomAD4 exome AF: 0.00536 AC: 328 AN: 61150 Hom.: 7 AF XY: 0.00535 AC XY: 165 AN XY: 30838

African (AFR) AF: 0.00335 AC: 4 AN: 1194

American (AMR) AF: 0.00500 AC: 10 AN: 2000

Ashkenazi Jewish (ASJ) AF: 0.00423 AC: 14 AN: 3308

East Asian (EAS) AF: 0.000206 AC: 1 AN: 4860

South Asian (SAS) AF: 0.00238 AC: 2 AN: 842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1434

Middle Eastern (MID) AF: 0.00694 AC: 3 AN: 432

European-Non Finnish (NFE) AF: 0.00638 AC: 272 AN: 42622

Other (OTH) AF: 0.00493 AC: 22 AN: 4458

GnomAD4 genome AF: 0.00685 AC: 836 AN: 122104 Hom.: 9 Cov.: 0 AF XY: 0.00682 AC XY: 397 AN XY: 58200

African (AFR) AF: 0.00223 AC: 66 AN: 29574

American (AMR) AF: 0.0171 AC: 210 AN: 12286

Ashkenazi Jewish (ASJ) AF: 0.00565 AC: 18 AN: 3186

East Asian (EAS) AF: 0.000471 AC: 2 AN: 4242

South Asian (SAS) AF: 0.00116 AC: 5 AN: 4328

European-Finnish (FIN) AF: 0.000861 AC: 5 AN: 5810

Middle Eastern (MID) AF: 0.00431 AC: 1 AN: 232

European-Non Finnish (NFE) AF: 0.00861 AC: 516 AN: 59912

Other (OTH) AF: 0.00749 AC: 13 AN: 1736

Alfa AF: 0.00 Hom.: 380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs60872763; hg19: chr2-204738050;