rs376916824
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000246.4(CIITA):c.1643G>A(p.Arg548Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000118 in 1,612,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R548L) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00012 ( 0 hom. )
Consequence
CIITA
NM_000246.4 missense
NM_000246.4 missense
Scores
1
7
6
Clinical Significance
Conservation
PhyloP100: 6.33
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| CIITA | NM_000246.4 | c.1643G>A | p.Arg548Gln | missense_variant | 11/20 | ENST00000324288.14 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| CIITA | ENST00000324288.14 | c.1643G>A | p.Arg548Gln | missense_variant | 11/20 | 1 | NM_000246.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000659 AC: 10AN: 151842Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000106 AC: 26AN: 244700Hom.: 0 AF XY: 0.0000971 AC XY: 13AN XY: 133836
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GnomAD4 exome AF: 0.000123 AC: 180AN: 1460258Hom.: 0 Cov.: 67 AF XY: 0.000116 AC XY: 84AN XY: 726458
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GnomAD4 genome ? AF: 0.0000659 AC: 10AN: 151842Hom.: 0 Cov.: 32 AF XY: 0.0000944 AC XY: 7AN XY: 74164
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
MHC class II deficiency Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 548 of the CIITA protein (p.Arg548Gln). This variant is present in population databases (rs376916824, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CIITA-related conditions. ClinVar contains an entry for this variant (Variation ID: 663834). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C35". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D
PrimateAI
Benign
T
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
0.34
ClinPred
T
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at