16-10877332-T-G

Variant names:

• chr16-10877332-T-G
• rs1361878318
• NM_000246.4:c.2T>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_000246.4(CIITA):​c.2T>G​(p.Met1?) variant causes a start lost 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CIITA NM_000246.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.97

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]

ENSG00000262151 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 25 codons. Genomic position: 10895302. Lost 0.022 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2T>G	p.Met1?	start_lost	Exon 1 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.2T>G	p.Met1?	start_lost	Exon 1 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Uncertain:1

Aug 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the CIITA mRNA. The next in-frame methionine is located at codon 25. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CIITA-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Benign	0.96
Eigen	Benign	0.048
Eigen_PC	Benign	0.013
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	-0.14	T
PROVEAN	Benign	-0.76	.;.;N;N
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.96
MutPred		0.98		Loss of catalytic residue at M1 (P = 0.0444);Loss of catalytic residue at M1 (P = 0.0444);Loss of catalytic residue at M1 (P = 0.0444);Loss of catalytic residue at M1 (P = 0.0444);
MVP		0.83
ClinPred		0.80	D
GERP RS		2.9
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs1361878318; hg19: chr16-10971189;