rs4774

chr16-10906991-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000246.4(CIITA):c.1499G>C(p.Gly500Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,610,818 control chromosomes in the GnomAD database, including 68,025 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G500S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (6096 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61929 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.811

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012209415).
• BP6: Variant 16-10906991-G-C is Benign according to our data. Variant chr16-10906991-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 317694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.1499G>C	p.Gly500Ala	missense_variant	11/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.1499G>C	p.Gly500Ala	missense_variant	11/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42294 AN: 151962 Hom.: 6082 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.258

GnomAD3 exomes AF: 0.297 AC: 73478 AN: 247744 Hom.: 11913 AF XY: 0.289 AC XY: 38862 AN XY: 134590

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.264

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.288 AC: 419593 AN: 1458738 Hom.: 61929 Cov.: 65 AF XY: 0.286 AC XY: 207725 AN XY: 725854

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.461

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.206

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.289

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.278 AC: 42344 AN: 152080 Hom.: 6096 Cov.: 32 AF XY: 0.279 AC XY: 20713 AN XY: 74334

Gnomad4 AFR AF: 0.258

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.157

Gnomad4 SAS AF: 0.249

Gnomad4 FIN AF: 0.230

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.261

Alfa AF: 0.288 Hom.: 4746

Bravo AF: 0.289

TwinsUK AF: 0.288 AC: 1069

ALSPAC AF: 0.286 AC: 1101

ESP6500AA AF: 0.257 AC: 1130

ESP6500EA AF: 0.292 AC: 2514

ExAC AF: 0.290 AC: 35238

Asia WGS AF: 0.266 AC: 924 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.282

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with MS -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2018	This variant is associated with the following publications: (PMID: 25992516, 20211854, 21614020, 19659749) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	4.7
Dann	Benign	0.18
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.40	T;T
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.39	T
Sift4G	Benign	1.0	T;T
Vest4		0.29
MPC		0.14
ClinPred		0.0077	T
GERP RS		-0.80
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs4774; hg19: chr16-11000848; COSMIC: COSV60853796; COSMIC: COSV60853796;