Genetic Variant CIITA:p.His824His (chr16-10907964-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000246.4(CIITA):c.2472C>T(p.His824His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,570,188 control chromosomes in the GnomAD database, including 672 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 46 hom., cov: 33)

Exomes 𝑓: 0.026 ( 626 hom. )

Consequence

CIITA
NM_000246.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.30

Publications

7 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

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=-0.64).

BP6

Variant 16-10907964-C-T is Benign according to our data. Variant chr16-10907964-C-T is described in ClinVar as Benign. ClinVar VariationId is 317713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.3 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0192 (2922/152322) while in subpopulation NFE AF = 0.0256 (1740/68022). AF 95% confidence interval is 0.0246. There are 46 homozygotes in GnomAd4. There are 1524 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 46 AR gene

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	UniProt
CIITA	NM_000246.4	MANE Select	c.2472C>T	p.His824His	synonymous	Exon 11 of 20	NP_000237.2
CIITA	NM_001286402.1		c.2475C>T	p.His825His	synonymous	Exon 11 of 20	NP_001273331.1	A0A087X2I7
CIITA	NM_001379332.1		c.2475C>T	p.His825His	synonymous	Exon 11 of 20	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2472C>T	p.His824His	synonymous	Exon 11 of 20	ENSP00000316328.8
CIITA	ENST00000381835.9	TSL:1	c.860-1019C>T		intron	N/A	ENSP00000371257.5	P33076-3
CIITA	ENST00000573309.5	TSL:1	n.2443C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2922

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00477

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.00876

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0720

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0256

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0214

AC:

4608

AN:

215586

AF XY:

0.0214

show subpopulations

Gnomad AFR exome

AF:

0.00561

Gnomad AMR exome

AF:

0.00823

Gnomad ASJ exome

AF:

0.00825

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0746

Gnomad NFE exome

AF:

0.0269

Gnomad OTH exome

AF:

0.0198

GnomAD4 exome

AF:

0.0258

AC:

36585

AN:

1417866

Hom.:

626

Cov.:

AF XY:

0.0252

AC XY:

17629

AN XY:

700630

show subpopulations

African (AFR)

AF:

0.00434

AC:

139

AN:

32030

American (AMR)

AF:

0.00862

AC:

338

AN:

39216

Ashkenazi Jewish (ASJ)

AF:

0.00876

AC:

202

AN:

23060

East Asian (EAS)

AF:

0.0000509

AC:

AN:

39282

South Asian (SAS)

AF:

0.000700

AC:

AN:

78604

European-Finnish (FIN)

AF:

0.0704

AC:

3624

AN:

51474

Middle Eastern (MID)

AF:

0.00271

AC:

AN:

5528

European-Non Finnish (NFE)

AF:

0.0284

AC:

30934

AN:

1090392

Other (OTH)

AF:

0.0219

AC:

1276

AN:

58280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2224

4448

6671

8895

11119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1196

2392

3588

4784

5980

<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:

0.0192

AC:

2922

AN:

152322

Hom.:

Cov.:

AF XY:

0.0205

AC XY:

1524

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00476

AC:

198

AN:

41588

American (AMR)

AF:

0.00875

AC:

134

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0720

AC:

763

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0256

AC:

1740

AN:

68022

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

146

292

439

585

731

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0191

Hom.:

Bravo

AF:

0.0146

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MHC class II deficiency (3)

CIITA-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

2.1

(source)

DANN

Benign

0.40

PhyloP100

-1.3

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over