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.2565G>A(p.Ala855Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 1,612,930 control chromosomes in the GnomAD database, including 5,059 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. A855A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.062 ( 370 hom., cov: 33)

Exomes 𝑓: 0.077 ( 4689 hom. )

Consequence

CIITA
NM_000246.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -5.02

Publications

14 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=-0.93).

BP6

Variant 16-10908057-G-A is Benign according to our data. Variant chr16-10908057-G-A is described in ClinVar as Benign. ClinVar VariationId is 317714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0809 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.2565G>A	p.Ala855Ala	synonymous	Exon 11 of 20	NP_000237.2
CIITA	NM_001286402.1		c.2568G>A	p.Ala856Ala	synonymous	Exon 11 of 20	NP_001273331.1
CIITA	NM_001379332.1		c.2568G>A	p.Ala856Ala	synonymous	Exon 11 of 20	NP_001366261.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2565G>A	p.Ala855Ala	synonymous	Exon 11 of 20	ENSP00000316328.8
CIITA	ENST00000573309.5	TSL:1	n.2536G>A		non_coding_transcript_exon	Exon 10 of 10
CIITA	ENST00000381835.9	TSL:1	c.860-926G>A		intron	N/A	ENSP00000371257.5

Frequencies

GnomAD3 genomes

AF:

0.0621

AC:

9450

AN:

152208

Hom.:

370

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0350

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0550

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0474

Gnomad FIN

AF:

0.0729

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0826

Gnomad OTH

AF:

0.0803

GnomAD2 exomes

AF:

0.0635

AC:

15567

AN:

245318

AF XY:

0.0655

show subpopulations

Gnomad AFR exome

AF:

0.0355

Gnomad AMR exome

AF:

0.0375

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.000666

Gnomad FIN exome

AF:

0.0734

Gnomad NFE exome

AF:

0.0863

Gnomad OTH exome

AF:

0.0727

GnomAD4 exome

AF:

0.0770

AC:

112457

AN:

1460604

Hom.:

4689

Cov.:

AF XY:

0.0772

AC XY:

56102

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.0361

AC:

1208

AN:

33466

American (AMR)

AF:

0.0397

AC:

1772

AN:

44604

Ashkenazi Jewish (ASJ)

AF:

0.0609

AC:

1591

AN:

26114

East Asian (EAS)

AF:

0.000832

AC:

AN:

39658

South Asian (SAS)

AF:

0.0540

AC:

4654

AN:

86150

European-Finnish (FIN)

AF:

0.0730

AC:

3878

AN:

53112

Middle Eastern (MID)

AF:

0.0968

AC:

558

AN:

5764

European-Non Finnish (NFE)

AF:

0.0847

AC:

94176

AN:

1111414

Other (OTH)

AF:

0.0760

AC:

4587

AN:

60322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6582

13164

19746

26328

32910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3396

6792

10188

13584

16980

<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:

0.0621

AC:

9461

AN:

152326

Hom.:

370

Cov.:

AF XY:

0.0618

AC XY:

4600

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.0352

AC:

1465

AN:

41580

American (AMR)

AF:

0.0549

AC:

840

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5184

South Asian (SAS)

AF:

0.0474

AC:

229

AN:

4832

European-Finnish (FIN)

AF:

0.0729

AC:

774

AN:

10616

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0827

AC:

5622

AN:

68016

Other (OTH)

AF:

0.0795

AC:

168

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

464

928

1393

1857

2321

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

220

330

440

550

<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:

0.0727

Hom.:

210

Bravo

AF:

0.0607

Asia WGS

AF:

0.0300

AC:

103

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

-0.93

CADD

Benign

0.082

(source)

DANN

Benign

0.50

PhyloP100

-5.0

Mutation Taster

=98/2

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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rs2229321

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