16-10910506-G-C

Variant names:

• chr16-10910506-G-C
• rs6498126
• NM_000246.4:c.2888+247G>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.2888+247G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.725 in 152,136 control chromosomes in the GnomAD database, including 40,744 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 0.73 (40744 hom., cov: 32)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.82
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.853 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2888+247G>C		intron_variant	Intron 13 of 19	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.2888+247G>C		intron_variant	Intron 13 of 19	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.725 AC: 110240 AN: 152018 Hom.: 40715 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.891

Gnomad AMR AF: 0.724

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.665

Gnomad SAS AF: 0.874

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.789

Gnomad OTH AF: 0.692

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.725 AC: 110321 AN: 152136 Hom.: 40744 Cov.: 32 AF XY: 0.729 AC XY: 54235 AN XY: 74364

African (AFR) AF: 0.584 AC: 24208 AN: 41480

American (AMR) AF: 0.724 AC: 11063 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 2354 AN: 3468

East Asian (EAS) AF: 0.665 AC: 3438 AN: 5168

South Asian (SAS) AF: 0.875 AC: 4225 AN: 4826

European-Finnish (FIN) AF: 0.841 AC: 8919 AN: 10608

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.789 AC: 53642 AN: 67982

Other (OTH) AF: 0.693 AC: 1463 AN: 2110

Alfa AF: 0.690 Hom.: 2178

Bravo AF: 0.707

Asia WGS AF: 0.797 AC: 2773 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.067
DANN	Benign	0.70
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6498126; hg19: chr16-11004363;