2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*544_*571delATATATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*544_*571delATATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00817 in 183,194 control chromosomes in the GnomAD database, including 50 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 0.011 (50 hom., cov: 0)
  • Exomes 𝑓: 0.0023 (0 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 = 0.0111 (1357/122098) while in subpopulation AFR AF = 0.0399 (1180/29578). AF 95% confidence interval is 0.038. There are 50 homozygotes in GnomAd4. There are 613 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1357 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.*544_*571delATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*581_*608delATATATATATATATATATATATATATAT		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.*544_*571delATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*544_*571delATATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*543delATATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1355 AN: 122106 Hom.: 50 Cov.: 0

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00692

Gnomad ASJ AF: 0.000628

Gnomad EAS AF: 0.00915

Gnomad SAS AF: 0.00299

Gnomad FIN AF: 0.000172

Gnomad MID AF: 0.00397

Gnomad NFE AF: 0.000401

Gnomad OTH AF: 0.00929

GnomAD4 exome AF: 0.00228 AC: 139 AN: 61096 Hom.: 0 AF XY: 0.00217 AC XY: 67 AN XY: 30812

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

African (AFR) AF: 0.0186 AC: 22 AN: 1184

American (AMR) AF: 0.00450 AC: 9 AN: 1998

Ashkenazi Jewish (ASJ) AF: 0.000908 AC: 3 AN: 3304

East Asian (EAS) AF: 0.00913 AC: 44 AN: 4820

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 432

European-Non Finnish (NFE) AF: 0.00108 AC: 46 AN: 42638

Other (OTH) AF: 0.00292 AC: 13 AN: 4446

⚠️ 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.

GnomAD4 genome AF: 0.0111 AC: 1357 AN: 122098 Hom.: 50 Cov.: 0 AF XY: 0.0105 AC XY: 613 AN XY: 58202

African (AFR) AF: 0.0399 AC: 1180 AN: 29578

American (AMR) AF: 0.00692 AC: 85 AN: 12288

Ashkenazi Jewish (ASJ) AF: 0.000628 AC: 2 AN: 3186

East Asian (EAS) AF: 0.00825 AC: 35 AN: 4242

South Asian (SAS) AF: 0.00300 AC: 13 AN: 4328

European-Finnish (FIN) AF: 0.000172 AC: 1 AN: 5808

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

European-Non Finnish (NFE) AF: 0.000401 AC: 24 AN: 59902

Other (OTH) AF: 0.00922 AC: 16 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;