rs4774

Positions:

chr16-10906991-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/18 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.

Frequency

Genomes: 𝑓 0.28 ( 6096 hom., cov: 32)

Exomes 𝑓: 0.29 ( 61929 hom. )

Consequence

CIITA
NM_000246.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 0.811

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
CIITA	NM_000246.4 linkuse as main transcript	c.1499G>C	p.Gly500Ala	missense_variant	11/20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14 linkuse as main transcript	c.1499G>C	p.Gly500Ala	missense_variant	11/20	1	NM_000246.4	ENSP00000316328	P4

Frequencies

GnomAD3 genomes

AF:

0.278

AC:

42294

AN:

151962

Hom.:

6082

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.286

AC XY:

207725

AN XY:

725854

show subpopulations

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.:

AF XY:

0.279

AC XY:

20713

AN XY:

74334

show subpopulations

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:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Genome-Nilou Lab	Jul 10, 2021	- -

not provided

Benign:2Other:1

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2018	This variant is associated with the following publications: (PMID: 25992516, 20211854, 21614020, 19659749) -
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. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.57

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

LIST_S2

Benign

0.40

T;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.39

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over