rs1139564

chr16-10924765-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -1.19

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 317747.Status of the report is criteria_provided_single_submitter, 1 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/exons	MANE	UniProt
CIITA	NM_000246.4	c.*910T>C		3_prime_UTR_variant	20/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.*910T>C		3_prime_UTR_variant	20/20	1	NM_000246.4	P4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.808

Gnomad4 OTH exome AF: 1.00

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

Gnomad4 AFR AF: 0.481

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.811

Gnomad4 EAS AF: 0.761

Gnomad4 SAS AF: 0.741

Gnomad4 FIN AF: 0.864

Gnomad4 NFE AF: 0.814

Gnomad4 OTH AF: 0.725

Alfa AF: 0.789 Hom.: 27183

Bravo AF: 0.702

Asia WGS AF: 0.742 AC: 2578 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1139564; hg19: chr16-11018622;