NM_000246.4:c.296-539T>C

Variant names:

• chr16-10898131-T-C
• rs8048002
• NM_000246.4:c.296-539T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000246.4(CIITA):​c.296-539T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,188 control chromosomes in the GnomAD database, including 1,387 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (1387 hom., cov: 31)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 11 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000246.4. 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
	CIITA	NM_000246.4	MANE Select	c.296-539T>C		intron	N/A	NP_000237.2
	CIITA	NM_001286402.1		c.296-539T>C		intron	N/A	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.296-539T>C		intron	N/A	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.296-539T>C		intron	N/A	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.296-539T>C		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000537380.1	TSL:1	n.296-539T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17449 AN: 152070 Hom.: 1382 Cov.: 31

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0665

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.0695

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0660

Gnomad OTH AF: 0.107

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.115 AC: 17486 AN: 152188 Hom.: 1387 Cov.: 31 AF XY: 0.117 AC XY: 8674 AN XY: 74398

African (AFR) AF: 0.203 AC: 8444 AN: 41518

American (AMR) AF: 0.0664 AC: 1016 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1535 AN: 5146

South Asian (SAS) AF: 0.145 AC: 697 AN: 4812

European-Finnish (FIN) AF: 0.0695 AC: 737 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0660 AC: 4491 AN: 68022

Other (OTH) AF: 0.108 AC: 229 AN: 2114

Alfa AF: 0.0616 Hom.: 110

Bravo AF: 0.118

Asia WGS AF: 0.202 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.3
DANN	Benign	0.53
PhyloP100		0.020
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: rs8048002; hg19: chr16-10991988;