NM_005214.5:c.*548_*571delATATATATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*548_*571delATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*548_*571delATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 180,208 control chromosomes in the GnomAD database, including 2,079 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 0.17 (2053 hom., cov: 0)
  • Exomes 𝑓: 0.036 (26 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 (EAS) allele frequency at 95% confidence interval = 0.268 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.*548_*571delATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*585_*608delATATATATATATATATATATATAT		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.*548_*571delATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*548_*571delATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*539delATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.170 AC: 20647 AN: 121284 Hom.: 2055 Cov.: 0

Gnomad AFR AF: 0.0833

Gnomad AMI AF: 0.0942

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.0920

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.138

GnomAD4 exome AF: 0.0357 AC: 2104 AN: 58936 Hom.: 26 AF XY: 0.0382 AC XY: 1138 AN XY: 29802

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

African (AFR) AF: 0.00945 AC: 11 AN: 1164

American (AMR) AF: 0.0443 AC: 85 AN: 1920

Ashkenazi Jewish (ASJ) AF: 0.0172 AC: 55 AN: 3196

East Asian (EAS) AF: 0.0778 AC: 350 AN: 4498

South Asian (SAS) AF: 0.0235 AC: 19 AN: 810

European-Finnish (FIN) AF: 0.0445 AC: 63 AN: 1416

Middle Eastern (MID) AF: 0.0143 AC: 6 AN: 420

European-Non Finnish (NFE) AF: 0.0337 AC: 1387 AN: 41216

Other (OTH) AF: 0.0298 AC: 128 AN: 4296

⚠️ 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: 0.170 AC: 20637 AN: 121272 Hom.: 2053 Cov.: 0 AF XY: 0.173 AC XY: 9985 AN XY: 57706

African (AFR) AF: 0.0832 AC: 2454 AN: 29500

American (AMR) AF: 0.211 AC: 2569 AN: 12202

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 378 AN: 3164

East Asian (EAS) AF: 0.281 AC: 1180 AN: 4200

South Asian (SAS) AF: 0.125 AC: 534 AN: 4286

European-Finnish (FIN) AF: 0.298 AC: 1687 AN: 5652

Middle Eastern (MID) AF: 0.100 AC: 23 AN: 230

European-Non Finnish (NFE) AF: 0.193 AC: 11498 AN: 59516

Other (OTH) AF: 0.138 AC: 239 AN: 1726

Alfa AF: 0.234 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 (auto)

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;