2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATATATATATATAT

Variant names:

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

Variant summary

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

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. 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. The gene CTLA4 is included in the ClinGen Criteria Specification Registry.

• 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
• 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: 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.*556_*571delATATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*593_*608delATATATATATATATAT		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.*556_*571delATATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*556_*571delATATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*531delATATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

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

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

African (AFR) AF: 0.00251 AC: 3 AN: 1194

American (AMR) AF: 0.00150 AC: 3 AN: 2002

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3304

East Asian (EAS) AF: 0.000206 AC: 1 AN: 4858

South Asian (SAS) AF: 0.00 AC: 0 AN: 840

European-Finnish (FIN) AF: 0.000697 AC: 1 AN: 1434

Middle Eastern (MID) AF: 0.00231 AC: 1 AN: 432

European-Non Finnish (NFE) AF: 0.000446 AC: 19 AN: 42598

Other (OTH) AF: 0.000899 AC: 4 AN: 4448

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

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

African (AFR) AF: 0.0149 AC: 438 AN: 29448

American (AMR) AF: 0.00840 AC: 103 AN: 12266

Ashkenazi Jewish (ASJ) AF: 0.0200 AC: 63 AN: 3156

East Asian (EAS) AF: 0.00189 AC: 8 AN: 4240

South Asian (SAS) AF: 0.00462 AC: 20 AN: 4326

European-Finnish (FIN) AF: 0.00709 AC: 41 AN: 5784

Middle Eastern (MID) AF: 0.0216 AC: 5 AN: 232

European-Non Finnish (NFE) AF: 0.0181 AC: 1078 AN: 59584

Other (OTH) AF: 0.0127 AC: 22 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
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;