16-10888488-G-C

Variant names:

• chr16-10888488-G-C
• rs8043545
• NM_000246.4:c.53-6794G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000246.4(CIITA):​c.53-6794G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.326 in 152,146 control chromosomes in the GnomAD database, including 8,969 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8969 hom., cov: 33)
  • Exomes 𝑓: 0.23 (0 hom.)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.346
• Publications: 13 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000262151 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.525 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.53-6794G>C		intron	N/A	NP_000237.2
	CIITA	NM_001286402.1		c.53-6794G>C		intron	N/A	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.53-6794G>C		intron	N/A	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.53-6794G>C		intron	N/A	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.53-6794G>C		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000537380.1	TSL:1	n.53-6794G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.326 AC: 49533 AN: 152004 Hom.: 8933 Cov.: 33

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.324

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.227 AC: 5 AN: 22 Hom.: 0 Cov.: 0 AF XY: 0.167 AC XY: 2 AN XY: 12

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.333 AC: 2 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.214 AC: 3 AN: 14

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.326 AC: 49625 AN: 152124 Hom.: 8969 Cov.: 33 AF XY: 0.324 AC XY: 24126 AN XY: 74374

African (AFR) AF: 0.461 AC: 19115 AN: 41488

American (AMR) AF: 0.225 AC: 3443 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 942 AN: 3472

East Asian (EAS) AF: 0.542 AC: 2801 AN: 5172

South Asian (SAS) AF: 0.324 AC: 1563 AN: 4822

European-Finnish (FIN) AF: 0.242 AC: 2558 AN: 10588

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18274 AN: 67978

Other (OTH) AF: 0.312 AC: 659 AN: 2114

Alfa AF: 0.171 Hom.: 332

Bravo AF: 0.327

Asia WGS AF: 0.418 AC: 1448 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.44
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs8043545; hg19: chr16-10982345;