16-10898095-A-G

Variant names:

• chr16-10898095-A-G
• rs4781015
• NM_000246.4:c.296-575A>G

Variant summary

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

The NM_000246.4(CIITA):​c.296-575A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 151,994 control chromosomes in the GnomAD database, including 35,808 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 0.66 (35808 hom., cov: 31)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.378
• Publications: 3 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.296-575A>G		intron_variant	Intron 3 of 19	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.296-575A>G		intron_variant	Intron 3 of 19	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.665 AC: 100961 AN: 151876 Hom.: 35808 Cov.: 31

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.540

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.847

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.793

Gnomad OTH AF: 0.698

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

GnomAD4 genome AF: 0.664 AC: 100989 AN: 151994 Hom.: 35808 Cov.: 31 AF XY: 0.665 AC XY: 49378 AN XY: 74304

African (AFR) AF: 0.460 AC: 19027 AN: 41406

American (AMR) AF: 0.539 AC: 8227 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2796 AN: 3468

East Asian (EAS) AF: 0.395 AC: 2041 AN: 5168

South Asian (SAS) AF: 0.742 AC: 3567 AN: 4806

European-Finnish (FIN) AF: 0.847 AC: 8965 AN: 10586

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.793 AC: 53906 AN: 67984

Other (OTH) AF: 0.695 AC: 1467 AN: 2112

Alfa AF: 0.733 Hom.: 52101

Bravo AF: 0.627

Asia WGS AF: 0.586 AC: 2037 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.4
DANN	Benign	0.74
PhyloP100		0.38
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: rs4781015; hg19: chr16-10991952;