2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATATATATATATATATAT

Variant names:

• chr2-203873327-CATATATATATAT-C
• rs60872763
• NM_005214.5:c.*560_*571delATATATATATAT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005214.5(CTLA4):​c.*560_*571delATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00579 in 182,584 control chromosomes in the GnomAD database, including 3 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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0087 (3 hom., cov: 0)
  • Exomes 𝑓: 0.00011 (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: Uncertain_significance. The variant received 0 ACMG points.

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.*560_*571delATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*597_*608delATATATATATAT		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.*560_*571delATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*560_*571delATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*527delATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1051 AN: 121396 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0203

Gnomad AMR AF: 0.00572

Gnomad ASJ AF: 0.00314

Gnomad EAS AF: 0.00141

Gnomad SAS AF: 0.00277

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.00400

Gnomad NFE AF: 0.00756

Gnomad OTH AF: 0.00581

GnomAD4 exome AF: 0.000114 AC: 7 AN: 61198 Hom.: 0 AF XY: 0.000130 AC XY: 4 AN XY: 30870

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

African (AFR) AF: 0.000838 AC: 1 AN: 1194

American (AMR) AF: 0.00 AC: 0 AN: 2002

Ashkenazi Jewish (ASJ) AF: 0.000302 AC: 1 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4854

South Asian (SAS) AF: 0.00 AC: 0 AN: 842

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 432

European-Non Finnish (NFE) AF: 0.000117 AC: 5 AN: 42668

Other (OTH) AF: 0.00 AC: 0 AN: 4458

⚠️ 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: 0.00866 AC: 1051 AN: 121386 Hom.: 3 Cov.: 0 AF XY: 0.00855 AC XY: 495 AN XY: 57874

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

African (AFR) AF: 0.0159 AC: 465 AN: 29328

American (AMR) AF: 0.00572 AC: 70 AN: 12242

Ashkenazi Jewish (ASJ) AF: 0.00314 AC: 10 AN: 3180

East Asian (EAS) AF: 0.00142 AC: 6 AN: 4240

South Asian (SAS) AF: 0.00278 AC: 12 AN: 4316

European-Finnish (FIN) AF: 0.00190 AC: 11 AN: 5792

Middle Eastern (MID) AF: 0.00435 AC: 1 AN: 230

European-Non Finnish (NFE) AF: 0.00756 AC: 450 AN: 59536

Other (OTH) AF: 0.00577 AC: 10 AN: 1734

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

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;