NM_000246.4:c.2888+2427A>G

Variant names:

• chr16-10912686-A-G
• rs11074938
• NM_000246.4:c.2888+2427A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000246.4(CIITA):​c.2888+2427A>G variant causes a intron change. The variant allele was found at a frequency of 0.559 in 152,076 control chromosomes in the GnomAD database, including 24,189 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 0.56 (24189 hom., cov: 33)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.72
• Publications: 18 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.685 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.2888+2427A>G		intron	N/A	NP_000237.2
	CIITA	NM_001286402.1		c.2891+2427A>G		intron	N/A	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.2891+2427A>G		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.2888+2427A>G		intron	N/A	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.1136+2427A>G		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000886127.1		c.2891+2427A>G		intron	N/A	ENSP00000556186.1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84931 AN: 151960 Hom.: 24175 Cov.: 33

Gnomad AFR AF: 0.503

Gnomad AMI AF: 0.675

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.512

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.665

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.598

Gnomad OTH AF: 0.526

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

GnomAD4 genome AF: 0.559 AC: 84977 AN: 152076 Hom.: 24189 Cov.: 33 AF XY: 0.559 AC XY: 41597 AN XY: 74356

African (AFR) AF: 0.503 AC: 20868 AN: 41478

American (AMR) AF: 0.428 AC: 6541 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1960 AN: 3468

East Asian (EAS) AF: 0.513 AC: 2643 AN: 5154

South Asian (SAS) AF: 0.705 AC: 3397 AN: 4818

European-Finnish (FIN) AF: 0.665 AC: 7044 AN: 10588

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.598 AC: 40651 AN: 67978

Other (OTH) AF: 0.524 AC: 1108 AN: 2114

Alfa AF: 0.570 Hom.: 63922

Bravo AF: 0.532

Asia WGS AF: 0.564 AC: 1964 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Benign	0.93
PhyloP100		3.7
Mutation Taster		=98/2	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: rs11074938; hg19: chr16-11006543;