rs4781016

Variant names:

• chr16-10902542-C-A
• rs4781016
• NM_000246.4:c.629-116C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000246.4(CIITA):​c.629-116C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.278 in 1,299,786 control chromosomes in the GnomAD database, including 52,704 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6092 hom., cov: 33)
  • Exomes 𝑓: 0.28 (46612 hom.)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 16-10902542-C-A is Benign according to our data. Variant chr16-10902542-C-A is described in ClinVar as Benign. ClinVar VariationId is 1184677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.629-116C>A		intron_variant	Intron 7 of 19	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.629-116C>A		intron_variant	Intron 7 of 19	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.276 AC: 42011 AN: 152034 Hom.: 6088 Cov.: 33

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.188

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.158

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.278 AC: 319425 AN: 1147634 Hom.: 46612 AF XY: 0.276 AC XY: 160229 AN XY: 580694

African (AFR) AF: 0.241 AC: 6563 AN: 27260

American (AMR) AF: 0.473 AC: 17982 AN: 38036

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 9301 AN: 23694

East Asian (EAS) AF: 0.209 AC: 7749 AN: 36996

South Asian (SAS) AF: 0.233 AC: 17636 AN: 75560

European-Finnish (FIN) AF: 0.215 AC: 10026 AN: 46718

Middle Eastern (MID) AF: 0.282 AC: 1323 AN: 4688

European-Non Finnish (NFE) AF: 0.278 AC: 234464 AN: 844746

Other (OTH) AF: 0.288 AC: 14381 AN: 49936

GnomAD4 genome AF: 0.276 AC: 42049 AN: 152152 Hom.: 6092 Cov.: 33 AF XY: 0.275 AC XY: 20458 AN XY: 74372

African (AFR) AF: 0.247 AC: 10238 AN: 41496

American (AMR) AF: 0.390 AC: 5955 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1334 AN: 3470

East Asian (EAS) AF: 0.158 AC: 820 AN: 5178

South Asian (SAS) AF: 0.231 AC: 1116 AN: 4826

European-Finnish (FIN) AF: 0.204 AC: 2166 AN: 10600

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.288 AC: 19564 AN: 67990

Other (OTH) AF: 0.276 AC: 585 AN: 2116

Alfa AF: 0.293 Hom.: 12133

Bravo AF: 0.289

Asia WGS AF: 0.257 AC: 894 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MHC class II deficiency Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.54
PhyloP100		1.3
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: rs4781016; hg19: chr16-10996399; COSMIC: COSV60861061; COSMIC: COSV60861061;