2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*546_*571delATATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*546_*571delATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0256 in 182,410 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.

• Frequency:
  • Genomes: 𝑓 0.031 (181 hom., cov: 0)
  • Exomes 𝑓: 0.014 (5 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.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.171 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.*546_*571delATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*583_*608delATATATATATATATATATATATATAT		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.*546_*571delATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*546_*571delATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*541delATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0314 AC: 3825 AN: 122008 Hom.: 180 Cov.: 0

Gnomad AFR AF: 0.0325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0511

Gnomad ASJ AF: 0.0333

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.0603

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0262

GnomAD4 exome AF: 0.0139 AC: 841 AN: 60412 Hom.: 5 AF XY: 0.0133 AC XY: 406 AN XY: 30470

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

African (AFR) AF: 0.0152 AC: 18 AN: 1188

American (AMR) AF: 0.0199 AC: 39 AN: 1956

Ashkenazi Jewish (ASJ) AF: 0.00921 AC: 30 AN: 3256

East Asian (EAS) AF: 0.0779 AC: 356 AN: 4572

South Asian (SAS) AF: 0.0217 AC: 18 AN: 830

European-Finnish (FIN) AF: 0.00209 AC: 3 AN: 1434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 430

European-Non Finnish (NFE) AF: 0.00794 AC: 336 AN: 42334

Other (OTH) AF: 0.00929 AC: 41 AN: 4412

⚠️ 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: 0.0313 AC: 3823 AN: 121998 Hom.: 181 Cov.: 0 AF XY: 0.0329 AC XY: 1916 AN XY: 58150

African (AFR) AF: 0.0325 AC: 962 AN: 29566

American (AMR) AF: 0.0510 AC: 626 AN: 12268

Ashkenazi Jewish (ASJ) AF: 0.0333 AC: 106 AN: 3186

East Asian (EAS) AF: 0.182 AC: 767 AN: 4214

South Asian (SAS) AF: 0.0608 AC: 262 AN: 4312

European-Finnish (FIN) AF: 0.00913 AC: 53 AN: 5804

Middle Eastern (MID) AF: 0.0172 AC: 4 AN: 232

European-Non Finnish (NFE) AF: 0.0167 AC: 998 AN: 59884

Other (OTH) AF: 0.0260 AC: 45 AN: 1734

Alfa AF: 0.0128 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;