rs2229320

chr16-10907886-G-Achr16-10907886-G-Cchr16-10907886-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000246.4(CIITA):c.2394G>A(p.Pro798=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,600,210 control chromosomes in the GnomAD database, including 35,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P798P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2609 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33191 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.40

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-10907886-G-A is Benign according to our data. Variant chr16-10907886-G-A is described in ClinVar as [Benign]. Clinvar id is 317710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.4 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.2394G>A	p.Pro798=	synonymous_variant	11/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.2394G>A	p.Pro798=	synonymous_variant	11/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25467 AN: 152108 Hom.: 2606 Cov.: 33

Gnomad AFR AF: 0.0491

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.301

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.176

GnomAD3 exomes AF: 0.211 AC: 49961 AN: 236446 Hom.: 5810 AF XY: 0.219 AC XY: 28139 AN XY: 128496

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.224

Gnomad EAS exome AF: 0.314

Gnomad SAS exome AF: 0.277

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.209

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.210 AC: 303453 AN: 1447984 Hom.: 33191 Cov.: 82 AF XY: 0.212 AC XY: 152615 AN XY: 719124

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.147

Gnomad4 ASJ exome AF: 0.217

Gnomad4 EAS exome AF: 0.295

Gnomad4 SAS exome AF: 0.280

Gnomad4 FIN exome AF: 0.253

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.167 AC: 25470 AN: 152226 Hom.: 2609 Cov.: 33 AF XY: 0.171 AC XY: 12745 AN XY: 74406

Gnomad4 AFR AF: 0.0490

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.210

Gnomad4 EAS AF: 0.302

Gnomad4 SAS AF: 0.285

Gnomad4 FIN AF: 0.254

Gnomad4 NFE AF: 0.205

Gnomad4 OTH AF: 0.174

Alfa AF: 0.186 Hom.: 1160

Bravo AF: 0.154

Asia WGS AF: 0.219 AC: 764 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.055
Dann	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229320; hg19: chr16-11001743; COSMIC: COSV60853804;