chr16-10907555-G-A

Variant names:

• chr16-10907555-G-A
• rs863223293
• NM_000246.4:c.2063G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000246.4(CIITA):​c.2063G>A​(p.Trp688*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CIITA NM_000246.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.89
• Publications: 1 publications found

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)

ENSG00000308110 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-10907555-G-A is Pathogenic according to our data. Variant chr16-10907555-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 9543.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.2063G>A	p.Trp688*	stop_gained	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2066G>A	p.Trp689*	stop_gained	Exon 11 of 20	NP_001273331.1
	CIITA	NM_001379332.1		c.2066G>A	p.Trp689*	stop_gained	Exon 11 of 20	NP_001366261.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2063G>A	p.Trp688*	stop_gained	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000573309.5	TSL:1	n.2034G>A		non_coding_transcript_exon	Exon 10 of 10
	CIITA	ENST00000381835.9	TSL:1	c.860-1428G>A		intron	N/A	ENSP00000371257.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 66

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency 1 Pathogenic:1

Feb 01, 2002

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

MHC class II deficiency Pathogenic:1

Dec 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp688*) in the CIITA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CIITA are known to be pathogenic (PMID: 8402893, 9099848, 26271388). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 9543). This variant is also known as c.2178G>A. This premature translational stop signal has been observed in individual(s) with CIITA-related conditions (PMID: 11862382).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Benign	0.67	D
PhyloP100		2.9
Vest4		0.85
GERP RS		4.3
Mutation Taster		=8/192	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863223293; hg19: chr16-11001412;