2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*552_*571delATATATATATATATATATAT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_005214.5(CTLA4):​c.*552_*571delATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0198 in 182,616 control chromosomes in the GnomAD database, including 57 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 0.028 (57 hom., cov: 0)
  • Exomes 𝑓: 0.0031 (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.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 is higher than 0.05.

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.*552_*571delATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*589_*608delATATATATATATATATATAT		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.*552_*571delATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*552_*571delATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*535delATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0282 AC: 3427 AN: 121712 Hom.: 56 Cov.: 0

Gnomad AFR AF: 0.0550

Gnomad AMI AF: 0.0414

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0379

Gnomad EAS AF: 0.0366

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.0476

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0268

GnomAD4 exome AF: 0.00310 AC: 189 AN: 60914 Hom.: 0 AF XY: 0.00319 AC XY: 98 AN XY: 30710

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

African (AFR) AF: 0.00846 AC: 10 AN: 1182

American (AMR) AF: 0.00252 AC: 5 AN: 1988

Ashkenazi Jewish (ASJ) AF: 0.00305 AC: 10 AN: 3276

East Asian (EAS) AF: 0.00650 AC: 31 AN: 4768

South Asian (SAS) AF: 0.00239 AC: 2 AN: 838

European-Finnish (FIN) AF: 0.00349 AC: 5 AN: 1432

Middle Eastern (MID) AF: 0.00233 AC: 1 AN: 430

European-Non Finnish (NFE) AF: 0.00270 AC: 115 AN: 42558

Other (OTH) AF: 0.00225 AC: 10 AN: 4442

⚠️ 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: 0.0282 AC: 3427 AN: 121702 Hom.: 57 Cov.: 0 AF XY: 0.0273 AC XY: 1583 AN XY: 58000

African (AFR) AF: 0.0550 AC: 1618 AN: 29424

American (AMR) AF: 0.0171 AC: 209 AN: 12254

Ashkenazi Jewish (ASJ) AF: 0.0379 AC: 120 AN: 3170

East Asian (EAS) AF: 0.0363 AC: 153 AN: 4220

South Asian (SAS) AF: 0.0130 AC: 56 AN: 4310

European-Finnish (FIN) AF: 0.0300 AC: 173 AN: 5758

Middle Eastern (MID) AF: 0.0517 AC: 12 AN: 232

European-Non Finnish (NFE) AF: 0.0168 AC: 1007 AN: 59808

Other (OTH) AF: 0.0266 AC: 46 AN: 1728

Alfa AF: 0.0185 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;