rs1139564

Variant names:

• chr16-10924765-T-C
• rs1139564
• NM_000246.4:c.*910T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000246.4(CIITA):​c.*910T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.718 in 152,242 control chromosomes in the GnomAD database, including 40,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40924 hom., cov: 34)
  • Exomes 𝑓: 0.83 (16 hom.)
• Consequence: CIITA NM_000246.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.19
• Publications: 16 publications found

Genes affected

CIITA (HGNC:7067): (class II major histocompatibility complex transactivator) This gene encodes a protein with an acidic transcriptional activation domain, 4 LRRs (leucine-rich repeats) and a GTP binding domain. The protein is located in the nucleus and acts as a positive regulator of class II major histocompatibility complex gene transcription, and is referred to as the "master control factor" for the expression of these genes. The protein also binds GTP and uses GTP binding to facilitate its own transport into the nucleus. Once in the nucleus it does not bind DNA but rather uses an intrinsic acetyltransferase (AT) activity to act in a coactivator-like fashion. Mutations in this gene have been associated with bare lymphocyte syndrome type II (also known as hereditary MHC class II deficiency or HLA class II-deficient combined immunodeficiency), increased susceptibility to rheumatoid arthritis, multiple sclerosis, and possibly myocardial infarction. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

CIITA Gene-Disease associations (from GenCC):

• MHC class II deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 16-10924765-T-C is Benign according to our data. Variant chr16-10924765-T-C is described in ClinVar as Benign. ClinVar VariationId is 317747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.*910T>C		3_prime_UTR_variant	Exon 20 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.*910T>C		3_prime_UTR_variant	Exon 20 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109218 AN: 152082 Hom.: 40904 Cov.: 34

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.805

Gnomad AMR AF: 0.785

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.741

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.726

GnomAD4 exome AF: 0.833 AC: 35 AN: 42 Hom.: 16 Cov.: 0 AF XY: 0.875 AC XY: 21 AN XY: 24

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 8 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.808 AC: 21 AN: 26

Other (OTH) AF: 1.00 AC: 6 AN: 6

GnomAD4 genome AF: 0.718 AC: 109282 AN: 152200 Hom.: 40924 Cov.: 34 AF XY: 0.720 AC XY: 53594 AN XY: 74414

African (AFR) AF: 0.481 AC: 19952 AN: 41496

American (AMR) AF: 0.785 AC: 12022 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2817 AN: 3472

East Asian (EAS) AF: 0.761 AC: 3938 AN: 5176

South Asian (SAS) AF: 0.741 AC: 3578 AN: 4830

European-Finnish (FIN) AF: 0.864 AC: 9147 AN: 10590

Middle Eastern (MID) AF: 0.636 AC: 187 AN: 294

European-Non Finnish (NFE) AF: 0.814 AC: 55375 AN: 68012

Other (OTH) AF: 0.725 AC: 1532 AN: 2112

Alfa AF: 0.777 Hom.: 43194

Bravo AF: 0.702

Asia WGS AF: 0.742 AC: 2578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MHC class II deficiency Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.56
DANN	Benign	0.56
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1139564; hg19: chr16-11018622;