16-10880448-C-T

Variant names:

• chr16-10880448-C-T
• rs12925158
• NM_000246.4:c.52+3066C>T

Variant summary

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

The NM_000246.4(CIITA):​c.52+3066C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 152,272 control chromosomes in the GnomAD database, including 293 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 0.031 (293 hom., cov: 32)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.571
• 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)

ENSG00000262151 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.52+3066C>T		intron_variant	Intron 1 of 19	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.52+3066C>T		intron_variant	Intron 1 of 19	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4691 AN: 152154 Hom.: 291 Cov.: 32

Gnomad AFR AF: 0.00471

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.273

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0803

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0258

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

GnomAD4 genome AF: 0.0308 AC: 4685 AN: 152272 Hom.: 293 Cov.: 32 AF XY: 0.0371 AC XY: 2759 AN XY: 74444

African (AFR) AF: 0.00467 AC: 194 AN: 41560

American (AMR) AF: 0.0135 AC: 207 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3468

East Asian (EAS) AF: 0.273 AC: 1411 AN: 5170

South Asian (SAS) AF: 0.132 AC: 636 AN: 4820

European-Finnish (FIN) AF: 0.0803 AC: 852 AN: 10608

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1259 AN: 68028

Other (OTH) AF: 0.0251 AC: 53 AN: 2112

Alfa AF: 0.0236 Hom.: 263

Bravo AF: 0.0233

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		0.57
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: rs12925158; hg19: chr16-10974305;