NM_000246.4:c.52+641C>G

Variant names:

• chr16-10878023-C-G
• rs12932187
• NM_000246.4:c.52+641C>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+641C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 152,118 control chromosomes in the GnomAD database, including 895 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 0.081 (895 hom., cov: 32)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

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 = 0.4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.52+641C>G		intron	N/A	NP_000237.2
	CIITA	NM_001286402.1		c.52+641C>G		intron	N/A	NP_001273331.1
	CIITA	NM_001379332.1		c.52+641C>G		intron	N/A	NP_001366261.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.52+641C>G		intron	N/A	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.52+641C>G		intron	N/A	ENSP00000371257.5
	CIITA	ENST00000537380.1	TSL:1	n.52+641C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0812 AC: 12335 AN: 151998 Hom.: 893 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0661

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.415

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0711

Gnomad OTH AF: 0.0809

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

GnomAD4 genome AF: 0.0810 AC: 12329 AN: 152118 Hom.: 895 Cov.: 32 AF XY: 0.0875 AC XY: 6507 AN XY: 74356

African (AFR) AF: 0.0381 AC: 1581 AN: 41506

American (AMR) AF: 0.0660 AC: 1008 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 293 AN: 3472

East Asian (EAS) AF: 0.414 AC: 2140 AN: 5166

South Asian (SAS) AF: 0.222 AC: 1068 AN: 4814

European-Finnish (FIN) AF: 0.108 AC: 1137 AN: 10564

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0712 AC: 4839 AN: 68000

Other (OTH) AF: 0.0791 AC: 167 AN: 2112

Alfa AF: 0.0315 Hom.: 21

Bravo AF: 0.0734

Asia WGS AF: 0.255 AC: 883 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	7.5
DANN	Benign	0.65
PhyloP100		0.35
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: rs12932187; hg19: chr16-10971880;