chr2-203873327-CATATATATATATATATATATAT-C

Variant names:

• chr2-203873327-CATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*550_*571delATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*550_*571delATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0332 in 182,254 control chromosomes in the GnomAD database, including 186 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 0.046 (186 hom., cov: 0)
  • Exomes 𝑓: 0.0080 (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 = 0.0783 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.*550_*571delATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*587_*608delATATATATATATATATATATAT		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.*550_*571delATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*550_*571delATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*537delATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 5555 AN: 121730 Hom.: 184 Cov.: 0

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.00501

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0355

Gnomad EAS AF: 0.0675

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0200

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.0339

Gnomad OTH AF: 0.0384

GnomAD4 exome AF: 0.00804 AC: 487 AN: 60536 Hom.: 0 AF XY: 0.00835 AC XY: 255 AN XY: 30536

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

African (AFR) AF: 0.0154 AC: 18 AN: 1170

American (AMR) AF: 0.00754 AC: 15 AN: 1990

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 19 AN: 3294

East Asian (EAS) AF: 0.0178 AC: 85 AN: 4762

South Asian (SAS) AF: 0.00595 AC: 5 AN: 840

European-Finnish (FIN) AF: 0.00280 AC: 4 AN: 1430

Middle Eastern (MID) AF: 0.00948 AC: 4 AN: 422

European-Non Finnish (NFE) AF: 0.00718 AC: 303 AN: 42218

Other (OTH) AF: 0.00771 AC: 34 AN: 4410

⚠️ 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: 0.0457 AC: 5560 AN: 121718 Hom.: 186 Cov.: 0 AF XY: 0.0447 AC XY: 2594 AN XY: 57992

African (AFR) AF: 0.0810 AC: 2386 AN: 29444

American (AMR) AF: 0.0364 AC: 446 AN: 12256

Ashkenazi Jewish (ASJ) AF: 0.0355 AC: 113 AN: 3182

East Asian (EAS) AF: 0.0673 AC: 284 AN: 4220

South Asian (SAS) AF: 0.0260 AC: 112 AN: 4312

European-Finnish (FIN) AF: 0.0200 AC: 116 AN: 5788

Middle Eastern (MID) AF: 0.0345 AC: 8 AN: 232

European-Non Finnish (NFE) AF: 0.0339 AC: 2026 AN: 59754

Other (OTH) AF: 0.0375 AC: 65 AN: 1732

Alfa AF: 0.0274 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;