2-203873327-CATATATATATATATATATATATATATATATATATATATATATATAT-CATATATATATATATATATATATATATATATATATATATATATATATAT

Variant names:

• chr2-203873327-C-CAT
• rs60872763
• NM_005214.5:c.*570_*571dupAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*570_*571dupAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. 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 0.00094 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• 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.*570_*571dupAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*607_*608dupAT		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.*570_*571dupAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*570_*571dupAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*515_*516insAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.000935 AC: 114 AN: 121914 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000780

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000571

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000470

Gnomad SAS AF: 0.000230

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 61238 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 30886

African (AFR) AF: 0.00 AC: 0 AN: 1196

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3314

East Asian (EAS) AF: 0.00 AC: 0 AN: 4860

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: 0.00 AC: 0 AN: 42694

Other (OTH) AF: 0.00 AC: 0 AN: 4464

GnomAD4 genome AF: 0.000935 AC: 114 AN: 121906 Hom.: 0 Cov.: 0 AF XY: 0.000757 AC XY: 44 AN XY: 58114

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

African (AFR) AF: 0.000779 AC: 23 AN: 29540

American (AMR) AF: 0.000570 AC: 7 AN: 12270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3182

East Asian (EAS) AF: 0.000472 AC: 2 AN: 4236

South Asian (SAS) AF: 0.000231 AC: 1 AN: 4328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5810

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 230

European-Non Finnish (NFE) AF: 0.00136 AC: 81 AN: 59778

Other (OTH) AF: 0.00 AC: 0 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;