NM_000246.4:c.2072C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000246.4(CIITA):c.2072C>A(p.Ala691Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,614,164 control chromosomes in the GnomAD database, including 573 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A691V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.017 ( 58 hom., cov: 33)

Exomes 𝑓: 0.013 ( 515 hom. )

Consequence

CIITA
NM_000246.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.966

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

MHC class II deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

CIITA links:

ENSG00000308110 (HGNC:):

ENSG00000308110 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023306608).

BP6

Variant 16-10907564-C-A is Benign according to our data. Variant chr16-10907564-C-A is described in ClinVar as Benign. ClinVar VariationId is 317702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4 link	c.2072C>A	p.Ala691Asp	missense_variant	Exon 11 of 20	ENST00000324288.14	NP_000237.2	P33076A0A0B4J1S1Q66X48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14 link	c.2072C>A	p.Ala691Asp	missense_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8		A0A0B4J1S1

Frequencies

GnomAD3 genomes

AF:

0.0170

AC:

2588

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.0181

Gnomad ASJ

AF:

0.0176

Gnomad EAS

AF:

0.131

Gnomad SAS

AF:

0.0337

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00703

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0223

AC:

5606

AN:

251120

AF XY:

0.0221

show subpopulations

Gnomad AFR exome

AF:

0.0208

Gnomad AMR exome

AF:

0.0150

Gnomad ASJ exome

AF:

0.0159

Gnomad EAS exome

AF:

0.134

Gnomad FIN exome

AF:

0.00601

Gnomad NFE exome

AF:

0.00817

Gnomad OTH exome

AF:

0.0197

GnomAD4 exome

AF:

0.0134

AC:

19573

AN:

1461872

Hom.:

515

Cov.:

AF XY:

0.0140

AC XY:

10193

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0192

AC:

643

AN:

33480

American (AMR)

AF:

0.0163

AC:

730

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0163

AC:

426

AN:

26136

East Asian (EAS)

AF:

0.133

AC:

5263

AN:

39700

South Asian (SAS)

AF:

0.0300

AC:

2590

AN:

86256

European-Finnish (FIN)

AF:

0.00581

AC:

310

AN:

53402

Middle Eastern (MID)

AF:

0.0175

AC:

101

AN:

5768

European-Non Finnish (NFE)

AF:

0.00747

AC:

8303

AN:

1112010

Other (OTH)

AF:

0.0200

AC:

1207

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1418

2835

4253

5670

7088

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

438

876

1314

1752

2190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0170

AC:

2583

AN:

152292

Hom.:

Cov.:

AF XY:

0.0175

AC XY:

1307

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.0194

AC:

805

AN:

41564

American (AMR)

AF:

0.0180

AC:

276

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0176

AC:

AN:

3470

East Asian (EAS)

AF:

0.131

AC:

676

AN:

5164

South Asian (SAS)

AF:

0.0336

AC:

162

AN:

4826

European-Finnish (FIN)

AF:

0.00320

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00701

AC:

477

AN:

68020

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

120

240

360

480

600

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0132

Hom.:

163

Bravo

AF:

0.0191

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.0191

AC:

ESP6500EA

AF:

0.00605

AC:

ExAC

AF:

0.0220

AC:

2673

Asia WGS

AF:

0.0920

AC:

317

AN:

3478

EpiCase

AF:

0.00938

EpiControl

AF:

0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:3

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

CIITA-related disorder

Benign:1

Sep 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.82

T;T

MetaRNN

Benign

0.0023

T;T

MetaSVM

Benign

-0.92

PhyloP100

0.97

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

.;N

REVEL

Benign

0.085

Sift

Benign

0.16

.;T

Sift4G

Uncertain

0.019

D;D

Vest4

0.54

MPC

0.33

ClinPred

0.0066

GERP RS

3.3

gMVP

0.56

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over