chr2-203873327-CATATATATATATATATATATATATATATAT-C

Variant names:

• chr2-203873327-CATATATATATATATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*542_*571delATATATATATATATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*542_*571delATATATATATATATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 183,302 control chromosomes in the GnomAD database, including 110 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 0.019 (109 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (1 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 = 0.0662 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.*542_*571delATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*579_*608delATATATATATATATATATATATATATATAT		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.*542_*571delATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*542_*571delATATATATATATATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*545delATATATATATATATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0186 AC: 2275 AN: 122130 Hom.: 109 Cov.: 0

Gnomad AFR AF: 0.0688

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.000235

Gnomad SAS AF: 0.000691

Gnomad FIN AF: 0.000516

Gnomad MID AF: 0.00397

Gnomad NFE AF: 0.000567

Gnomad OTH AF: 0.0162

GnomAD4 exome AF: 0.00136 AC: 83 AN: 61182 Hom.: 1 AF XY: 0.00123 AC XY: 38 AN XY: 30876

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

African (AFR) AF: 0.0325 AC: 38 AN: 1170

American (AMR) AF: 0.00500 AC: 10 AN: 2002

Ashkenazi Jewish (ASJ) AF: 0.00363 AC: 12 AN: 3304

East Asian (EAS) AF: 0.000206 AC: 1 AN: 4854

South Asian (SAS) AF: 0.00119 AC: 1 AN: 842

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1434

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

European-Non Finnish (NFE) AF: 0.000258 AC: 11 AN: 42688

Other (OTH) AF: 0.00224 AC: 10 AN: 4458

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000275437), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0186 AC: 2272 AN: 122120 Hom.: 109 Cov.: 0 AF XY: 0.0185 AC XY: 1079 AN XY: 58194

African (AFR) AF: 0.0687 AC: 2033 AN: 29594

American (AMR) AF: 0.0102 AC: 125 AN: 12286

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 44 AN: 3188

East Asian (EAS) AF: 0.000236 AC: 1 AN: 4242

South Asian (SAS) AF: 0.000693 AC: 3 AN: 4328

European-Finnish (FIN) AF: 0.000516 AC: 3 AN: 5810

Middle Eastern (MID) AF: 0.00431 AC: 1 AN: 232

European-Non Finnish (NFE) AF: 0.000568 AC: 34 AN: 59904

Other (OTH) AF: 0.0161 AC: 28 AN: 1738

Alfa AF: 0.00 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;