chr2-203873327-CATATATATATATATATAT-C

Variant names:

• chr2-203873327-CATATATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*554_*571delATATATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*554_*571delATATATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.012 in 182,656 control chromosomes in the GnomAD database, including 32 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 0.018 (32 hom., cov: 0)
  • Exomes 𝑓: 0.00084 (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

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

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0175 (2133/121632) while in subpopulation AFR AF = 0.0311 (915/29378). AF 95% confidence interval is 0.0295. There are 32 homozygotes in GnomAd4. There are 915 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2133 Unknown,AD gene.

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.*554_*571delATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*591_*608delATATATATATATATATAT		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.*554_*571delATATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*554_*571delATATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*533delATATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2128 AN: 121640 Hom.: 32 Cov.: 0

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0154

Gnomad EAS AF: 0.00352

Gnomad SAS AF: 0.00161

Gnomad FIN AF: 0.00241

Gnomad MID AF: 0.00400

Gnomad NFE AF: 0.0143

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.000836 AC: 51 AN: 61024 Hom.: 0 AF XY: 0.000813 AC XY: 25 AN XY: 30766

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

African (AFR) AF: 0.00168 AC: 2 AN: 1194

American (AMR) AF: 0.00150 AC: 3 AN: 1998

Ashkenazi Jewish (ASJ) AF: 0.000303 AC: 1 AN: 3300

East Asian (EAS) AF: 0.00103 AC: 5 AN: 4836

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

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

Middle Eastern (MID) AF: 0.00234 AC: 1 AN: 428

European-Non Finnish (NFE) AF: 0.000846 AC: 36 AN: 42550

Other (OTH) AF: 0.000450 AC: 2 AN: 4442

⚠️ 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: 0.0175 AC: 2133 AN: 121632 Hom.: 32 Cov.: 0 AF XY: 0.0158 AC XY: 915 AN XY: 58010

African (AFR) AF: 0.0311 AC: 915 AN: 29378

American (AMR) AF: 0.0105 AC: 129 AN: 12266

Ashkenazi Jewish (ASJ) AF: 0.0154 AC: 49 AN: 3174

East Asian (EAS) AF: 0.00354 AC: 15 AN: 4242

South Asian (SAS) AF: 0.00162 AC: 7 AN: 4328

European-Finnish (FIN) AF: 0.00241 AC: 14 AN: 5802

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

European-Non Finnish (NFE) AF: 0.0143 AC: 853 AN: 59724

Other (OTH) AF: 0.0156 AC: 27 AN: 1728

Alfa AF: 0.0108 Hom.: 380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.8

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;