2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*536_*571delATATATATATATATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*536_*571delATATATATATATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 183,336 control chromosomes in the GnomAD database, including 13 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 0.0050 (11 hom., cov: 0)
  • Exomes 𝑓: 0.0012 (2 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 afr. GnomAd4 allele frequency = 0.00502 (613/122108) while in subpopulation AFR AF = 0.0183 (542/29582). AF 95% confidence interval is 0.017. There are 11 homozygotes in GnomAd4. There are 299 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 613 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.*536_*571delATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*573_*608delATATATATATATATATATATATATATATATATATAT		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.*536_*571delATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*536_*571delATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*551delATATATATATATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 612 AN: 122118 Hom.: 11 Cov.: 0

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00282

Gnomad EAS AF: 0.000235

Gnomad SAS AF: 0.000460

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000300

Gnomad OTH AF: 0.00465

GnomAD4 exome AF: 0.00122 AC: 75 AN: 61228 Hom.: 2 AF XY: 0.00117 AC XY: 36 AN XY: 30882

African (AFR) AF: 0.0176 AC: 21 AN: 1196

American (AMR) AF: 0.00300 AC: 6 AN: 2002

Ashkenazi Jewish (ASJ) AF: 0.00332 AC: 11 AN: 3310

East Asian (EAS) AF: 0.00 AC: 0 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: 0.00463 AC: 2 AN: 432

European-Non Finnish (NFE) AF: 0.000515 AC: 22 AN: 42688

Other (OTH) AF: 0.00246 AC: 11 AN: 4464

GnomAD4 genome AF: 0.00502 AC: 613 AN: 122108 Hom.: 11 Cov.: 0 AF XY: 0.00514 AC XY: 299 AN XY: 58200

African (AFR) AF: 0.0183 AC: 542 AN: 29582

American (AMR) AF: 0.00269 AC: 33 AN: 12290

Ashkenazi Jewish (ASJ) AF: 0.00282 AC: 9 AN: 3186

East Asian (EAS) AF: 0.000236 AC: 1 AN: 4242

South Asian (SAS) AF: 0.000462 AC: 2 AN: 4328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.000300 AC: 18 AN: 59904

Other (OTH) AF: 0.00461 AC: 8 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

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;