rs2228238

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000246.4(CIITA):c.2676G>A(p.Thr892=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.697 in 1,613,932 control chromosomes in the GnomAD database, including 395,596 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.65 ( 33146 hom., cov: 33)

Exomes 𝑓: 0.70 ( 362450 hom. )

Consequence

CIITA
NM_000246.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -1.65

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 16-10909047-G-A is Benign according to our data. Variant chr16-10909047-G-A is described in ClinVar as [Benign]. Clinvar id is 317717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10909047-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.65 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4 linkuse as main transcript	c.2676G>A	p.Thr892=	synonymous_variant	12/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14 linkuse as main transcript	c.2676G>A	p.Thr892=	synonymous_variant	12/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes

AF:

0.653

AC:

99256

AN:

152020

Hom.:

33143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.518

Gnomad AMI

AF:

0.700

Gnomad AMR

AF:

0.602

Gnomad ASJ

AF:

0.717

Gnomad EAS

AF:

0.841

Gnomad SAS

AF:

0.744

Gnomad FIN

AF:

0.770

Gnomad MID

AF:

0.669

Gnomad NFE

AF:

0.703

Gnomad OTH

AF:

0.680

GnomAD3 exomes

AF:

0.682

AC:

171164

AN:

250960

Hom.:

59720

AF XY:

0.695

AC XY:

94314

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.508

Gnomad AMR exome

AF:

0.505

Gnomad ASJ exome

AF:

0.704

Gnomad EAS exome

AF:

0.854

Gnomad SAS exome

AF:

0.729

Gnomad FIN exome

AF:

0.763

Gnomad NFE exome

AF:

0.703

Gnomad OTH exome

AF:

0.689

GnomAD4 exome

AF:

0.702

AC:

1025914

AN:

1461794

Hom.:

362450

Cov.:

AF XY:

0.704

AC XY:

512031

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.508

Gnomad4 AMR exome

AF:

0.514

Gnomad4 ASJ exome

AF:

0.708

Gnomad4 EAS exome

AF:

0.793

Gnomad4 SAS exome

AF:

0.735

Gnomad4 FIN exome

AF:

0.756

Gnomad4 NFE exome

AF:

0.707

Gnomad4 OTH exome

AF:

0.690

GnomAD4 genome

AF:

0.653

AC:

99294

AN:

152138

Hom.:

33146

Cov.:

AF XY:

0.655

AC XY:

48714

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.517

Gnomad4 AMR

AF:

0.601

Gnomad4 ASJ

AF:

0.717

Gnomad4 EAS

AF:

0.841

Gnomad4 SAS

AF:

0.744

Gnomad4 FIN

AF:

0.770

Gnomad4 NFE

AF:

0.703

Gnomad4 OTH

AF:

0.677

Alfa

AF:

0.678

Hom.:

17782

Bravo

AF:

0.631

Asia WGS

AF:

0.720

AC:

2505

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

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 -

not provided

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

Cadd

Benign

0.58

Dann

Benign

0.44

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over