rs4774

Variant names:

• chr16-10906991-G-C
• rs4774
• NM_000246.4:c.1499G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-10906991-G-C
• chr16-10906991-G-T

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.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. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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:8 O:1
• Conservation: PhyloP100: 0.811
• Publications: 72 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 (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 Benign/Likely_benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.1499G>C	p.Gly500Ala	missense_variant	Exon 11 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.1499G>C	p.Gly500Ala	missense_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8

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

GnomAD2 exomes AF: 0.297 AC: 73478 AN: 247744 AF XY: 0.289

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 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

African (AFR) AF: 0.257 AC: 8612 AN: 33476

American (AMR) AF: 0.461 AC: 20606 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7405 AN: 26134

East Asian (EAS) AF: 0.206 AC: 8181 AN: 39700

South Asian (SAS) AF: 0.259 AC: 22342 AN: 86258

European-Finnish (FIN) AF: 0.244 AC: 12273 AN: 50314

Middle Eastern (MID) AF: 0.250 AC: 1444 AN: 5768

European-Non Finnish (NFE) AF: 0.289 AC: 321378 AN: 1111984

Other (OTH) AF: 0.287 AC: 17352 AN: 60380

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

African (AFR) AF: 0.258 AC: 10689 AN: 41506

American (AMR) AF: 0.363 AC: 5547 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3468

East Asian (EAS) AF: 0.157 AC: 808 AN: 5146

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4828

European-Finnish (FIN) AF: 0.230 AC: 2431 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19818 AN: 67954

Other (OTH) AF: 0.261 AC: 550 AN: 2106

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:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 09, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

Aug 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25992516, 20211854, 21614020, 19659749) -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
PhyloP100		0.81
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	.;N
REVEL	Benign	0.26
Sift	Benign	0.84	.;T
Sift4G	Benign	1.0	T;T
Vest4		0.29
MPC		0.14
ClinPred		0.0077	T
GERP RS		-0.80
gMVP		0.68
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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