rs4781011

Variant names:

• chr16-10881454-T-G
• rs4781011
• NM_000246.4:c.52+4072T>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+4072T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.619 in 152,044 control chromosomes in the GnomAD database, including 31,038 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 0.62 (31038 hom., cov: 32)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.337
• Publications: 37 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.733 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.52+4072T>G		intron_variant	Intron 1 of 19	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.52+4072T>G		intron_variant	Intron 1 of 19	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.619 AC: 94077 AN: 151926 Hom.: 31040 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.733

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.738

Gnomad OTH AF: 0.650

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

GnomAD4 genome AF: 0.619 AC: 94107 AN: 152044 Hom.: 31038 Cov.: 32 AF XY: 0.612 AC XY: 45499 AN XY: 74300

African (AFR) AF: 0.483 AC: 20004 AN: 41444

American (AMR) AF: 0.512 AC: 7830 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.733 AC: 2542 AN: 3470

East Asian (EAS) AF: 0.124 AC: 640 AN: 5180

South Asian (SAS) AF: 0.592 AC: 2850 AN: 4818

European-Finnish (FIN) AF: 0.733 AC: 7761 AN: 10586

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.738 AC: 50178 AN: 67958

Other (OTH) AF: 0.647 AC: 1362 AN: 2104

Alfa AF: 0.691 Hom.: 97774

Bravo AF: 0.594

Asia WGS AF: 0.426 AC: 1485 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.3
DANN	Benign	0.73
PhyloP100		0.34
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: rs4781011; hg19: chr16-10975311;