Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000246.4(CIITA):c.2676G>A(p.Thr892Thr) 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:6O:1

Conservation

PhyloP100: -1.65

Publications

20 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 -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 VariationId is 317717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CIITA	NM_000246.4	MANE Select	c.2676G>A	p.Thr892Thr	synonymous	Exon 12 of 20	NP_000237.2
CIITA	NM_001286402.1		c.2679G>A	p.Thr893Thr	synonymous	Exon 12 of 20	NP_001273331.1
CIITA	NM_001379332.1		c.2679G>A	p.Thr893Thr	synonymous	Exon 12 of 20	NP_001366261.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2676G>A	p.Thr892Thr	synonymous	Exon 12 of 20	ENSP00000316328.8
CIITA	ENST00000381835.9	TSL:1	c.924G>A	p.Thr308Thr	synonymous	Exon 10 of 18	ENSP00000371257.5
CIITA	ENST00000537380.1	TSL:1	n.1007-1141G>A		intron	N/A

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

GnomAD2 exomes

AF:

0.682

AC:

171164

AN:

250960

AF XY:

0.695

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 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

African (AFR)

AF:

0.508

AC:

17003

AN:

33478

American (AMR)

AF:

0.514

AC:

22972

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.708

AC:

18498

AN:

26134

East Asian (EAS)

AF:

0.793

AC:

31499

AN:

39700

South Asian (SAS)

AF:

0.735

AC:

63371

AN:

86256

European-Finnish (FIN)

AF:

0.756

AC:

40395

AN:

53410

Middle Eastern (MID)

AF:

0.711

AC:

4098

AN:

5766

European-Non Finnish (NFE)

AF:

0.707

AC:

786404

AN:

1111938

Other (OTH)

AF:

0.690

AC:

41674

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

18878

37755

56633

75510

94388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19752

39504

59256

79008

98760

<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:

0.653

AC:

99294

AN:

152138

Hom.:

33146

Cov.:

AF XY:

0.655

AC XY:

48714

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.517

AC:

21461

AN:

41492

American (AMR)

AF:

0.601

AC:

9188

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.717

AC:

2487

AN:

3470

East Asian (EAS)

AF:

0.841

AC:

4356

AN:

5178

South Asian (SAS)

AF:

0.744

AC:

3588

AN:

4820

European-Finnish (FIN)

AF:

0.770

AC:

8155

AN:

10592

Middle Eastern (MID)

AF:

0.682

AC:

199

AN:

292

European-Non Finnish (NFE)

AF:

0.703

AC:

47792

AN:

67994

Other (OTH)

AF:

0.677

AC:

1430

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1723

3447

5170

6894

8617

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

808

1616

2424

3232

4040

<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:

0.678

Hom.:

17782

Bravo

AF:

0.631

Asia WGS

AF:

0.720

AC:

2505

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MHC class II deficiency (4)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.58

(source)

DANN

Benign

0.44

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over