chr2-203873327-CATATATATATATAT-C

Variant names:

• chr2-203873327-CATATATATATATAT-C
• rs60872763
• NM_005214.5:c.*558_*571delATATATATATATAT

Variant summary

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

The NM_005214.5(CTLA4):​c.*558_*571delATATATATATATAT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 183,066 control chromosomes in the GnomAD database, including 2 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 0.0045 (2 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00454 (553/121880) while in subpopulation AFR AF = 0.00915 (270/29512). AF 95% confidence interval is 0.00825. There are 2 homozygotes in GnomAd4. There are 254 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 553 AD,Unknown 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.*558_*571delATATATATATATAT		3_prime_UTR	Exon 4 of 4	NP_005205.2
	CTLA4	NM_001037631.3		c.*595_*608delATATATATATATAT		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.*558_*571delATATATATATATAT		3_prime_UTR	Exon 4 of 4	ENSP00000497102.1	P16410-1
	CTLA4	ENST00000696479.1		c.*558_*571delATATATATATATAT		3_prime_UTR	Exon 5 of 5	ENSP00000512655.1	A0A8Q3SIR7
	CTLA4	ENST00000696049.1		c.*516_*529delATATATATATATAT		downstream_gene	N/A	ENSP00000512353.1	A0A8Q3WKZ2

Frequencies

GnomAD3 genomes AF: 0.00454 AC: 553 AN: 121890 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.00913

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00277

Gnomad ASJ AF: 0.00790

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00185

Gnomad FIN AF: 0.000344

Gnomad MID AF: 0.0198

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00523

GnomAD4 exome AF: 0.000278 AC: 17 AN: 61186 Hom.: 0 AF XY: 0.000227 AC XY: 7 AN XY: 30866

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

African (AFR) AF: 0.000839 AC: 1 AN: 1192

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

Ashkenazi Jewish (ASJ) AF: 0.000604 AC: 2 AN: 3312

East Asian (EAS) AF: 0.00 AC: 0 AN: 4858

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

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

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

European-Non Finnish (NFE) AF: 0.000234 AC: 10 AN: 42652

Other (OTH) AF: 0.000672 AC: 3 AN: 4462

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000175415), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00454 AC: 553 AN: 121880 Hom.: 2 Cov.: 0 AF XY: 0.00437 AC XY: 254 AN XY: 58088

African (AFR) AF: 0.00915 AC: 270 AN: 29512

American (AMR) AF: 0.00277 AC: 34 AN: 12274

Ashkenazi Jewish (ASJ) AF: 0.00790 AC: 25 AN: 3166

East Asian (EAS) AF: 0.00118 AC: 5 AN: 4242

South Asian (SAS) AF: 0.00185 AC: 8 AN: 4318

European-Finnish (FIN) AF: 0.000344 AC: 2 AN: 5806

Middle Eastern (MID) AF: 0.0172 AC: 4 AN: 232

European-Non Finnish (NFE) AF: 0.00328 AC: 196 AN: 59796

Other (OTH) AF: 0.00518 AC: 9 AN: 1736

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;