2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*532_*571delATATATATATATATATATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*532_*571delATATATATATATATATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 182,636 control chromosomes in the GnomAD database, with no homozygous occurrence. 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.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0016 (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

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000287 (35/122104) while in subpopulation AMR AF = 0.000326 (4/12280). AF 95% confidence interval is 0.000111. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 35 Unknown,AD 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.*532_*571delATATATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*569_*608delATATATATATATATATATATATATATATATATATATATAT		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.*532_*571delATATATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*532_*571delATATATATATATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*555delATATATATATATATATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.000287 AC: 35 AN: 122104 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000135

Gnomad AMI AF: 0.0251

Gnomad AMR AF: 0.000326

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.000172

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000835

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00162 AC: 98 AN: 60532 Hom.: 0 AF XY: 0.00164 AC XY: 50 AN XY: 30536

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

African (AFR) AF: 0.00168 AC: 2 AN: 1190

American (AMR) AF: 0.00101 AC: 2 AN: 1976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3280

East Asian (EAS) AF: 0.00124 AC: 6 AN: 4834

South Asian (SAS) AF: 0.00 AC: 0 AN: 838

European-Finnish (FIN) AF: 0.00283 AC: 4 AN: 1414

Middle Eastern (MID) AF: 0.00237 AC: 1 AN: 422

European-Non Finnish (NFE) AF: 0.00183 AC: 77 AN: 42158

Other (OTH) AF: 0.00136 AC: 6 AN: 4420

⚠️ 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: 0.000287 AC: 35 AN: 122104 Hom.: 0 Cov.: 0 AF XY: 0.000258 AC XY: 15 AN XY: 58178

African (AFR) AF: 0.000135 AC: 4 AN: 29538

American (AMR) AF: 0.000326 AC: 4 AN: 12280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3186

East Asian (EAS) AF: 0.00 AC: 0 AN: 4260

South Asian (SAS) AF: 0.000230 AC: 1 AN: 4344

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.0000835 AC: 5 AN: 59916

Other (OTH) AF: 0.00 AC: 0 AN: 1722

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;