2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*556_*571delATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*556_*571delATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 182,678 control chromosomes in the GnomAD database, including 5 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (5 hom., cov: 0)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: CTLA4 NM_005214.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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]

ACMG classification

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

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0147 (1786/121568) while in subpopulation NFE AF = 0.0181 (1078/59584). AF 95% confidence interval is 0.0172. There are 5 homozygotes in GnomAd4. There are 800 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1786 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTLA4	NM_005214.5	c.*556_*571delATATATATATATATAT		3_prime_UTR_variant	Exon 4 of 4	ENST00000648405.2	NP_005205.2
CTLA4	NM_001037631.3	c.*593_*608delATATATATATATATAT		3_prime_UTR_variant	Exon 3 of 3		NP_001032720.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTLA4	ENST00000648405.2	c.*556_*571delATATATATATATATAT		3_prime_UTR_variant	Exon 4 of 4		NM_005214.5	ENSP00000497102.1
CTLA4	ENST00000696479.1	c.*556_*571delATATATATATATATAT		3_prime_UTR_variant	Exon 5 of 5			ENSP00000512655.1
CTLA4	ENST00000696049.1	c.*516_*531delATATATATATATATAT		downstream_gene_variant				ENSP00000512353.1
CTLA4	ENST00000427473.3	n.*238_*253delATATATATATATATAT		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1786 AN: 121578 Hom.: 5 Cov.: 0

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.0100

Gnomad AMR AF: 0.00840

Gnomad ASJ AF: 0.0200

Gnomad EAS AF: 0.00188

Gnomad SAS AF: 0.00461

Gnomad FIN AF: 0.00709

Gnomad MID AF: 0.0198

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0128

GnomAD4 exome AF: 0.000524 AC: 32 AN: 61110 Hom.: 0 AF XY: 0.000519 AC XY: 16 AN XY: 30814

Gnomad4 AFR exome AF: 0.00251 AC: 3 AN: 1194

Gnomad4 AMR exome AF: 0.00150 AC: 3 AN: 2002

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 3304

Gnomad4 EAS exome AF: 0.000206 AC: 1 AN: 4858

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 840

Gnomad4 FIN exome AF: 0.000697 AC: 1 AN: 1434

Gnomad4 NFE exome AF: 0.000446 AC: 19 AN: 42598

Gnomad4 Remaining exome AF: 0.000899 AC: 4 AN: 4448

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0147 AC: 1786 AN: 121568 Hom.: 5 Cov.: 0 AF XY: 0.0138 AC XY: 800 AN XY: 57970

Gnomad4 AFR AF: 0.0149 AC: 0.0148737 AN: 0.0148737

Gnomad4 AMR AF: 0.00840 AC: 0.0083972 AN: 0.0083972

Gnomad4 ASJ AF: 0.0200 AC: 0.019962 AN: 0.019962

Gnomad4 EAS AF: 0.00189 AC: 0.00188679 AN: 0.00188679

Gnomad4 SAS AF: 0.00462 AC: 0.00462321 AN: 0.00462321

Gnomad4 FIN AF: 0.00709 AC: 0.00708852 AN: 0.00708852

Gnomad4 NFE AF: 0.0181 AC: 0.0180921 AN: 0.0180921

Gnomad4 OTH AF: 0.0127 AC: 0.0126874 AN: 0.0126874

Alfa AF: 0.00 Hom.: 380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs60872763; hg19: chr2-204738050;