chr16-10877617-A-G

Variant names:

• chr16-10877617-A-G
• rs12928665
• NM_000246.4:c.52+235A>G

Variant summary

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

The NM_000246.4(CIITA):​c.52+235A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,000 control chromosomes in the GnomAD database, including 4,581 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 0.23 (4581 hom., cov: 32)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• Publications: 9 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

ENSG00000262151 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 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.52+235A>G		intron	N/A	NP_000237.2
	CIITA	NM_001286402.1		c.52+235A>G		intron	N/A	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.52+235A>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.52+235A>G		intron	N/A	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.52+235A>G		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000537380.1	TSL:1	n.52+235A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35230 AN: 151882 Hom.: 4576 Cov.: 32

Gnomad AFR AF: 0.162

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.251

Gnomad OTH AF: 0.226

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

GnomAD4 genome AF: 0.232 AC: 35243 AN: 152000 Hom.: 4581 Cov.: 32 AF XY: 0.233 AC XY: 17313 AN XY: 74276

African (AFR) AF: 0.162 AC: 6725 AN: 41480

American (AMR) AF: 0.180 AC: 2748 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 881 AN: 3468

East Asian (EAS) AF: 0.573 AC: 2947 AN: 5140

South Asian (SAS) AF: 0.335 AC: 1608 AN: 4804

European-Finnish (FIN) AF: 0.240 AC: 2538 AN: 10564

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.251 AC: 17057 AN: 67936

Other (OTH) AF: 0.230 AC: 486 AN: 2112

Alfa AF: 0.245 Hom.: 21525

Bravo AF: 0.220

Asia WGS AF: 0.399 AC: 1384 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.7
DANN	Benign	0.24
PhyloP100		2.3
PromoterAI		0.023	Neutral
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: rs12928665; hg19: chr16-10971474;