16-10907837-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000246.4(CIITA):c.2345T>C(p.Val782Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 1,613,464 control chromosomes in the GnomAD database, including 5,099 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V782V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.062 ( 366 hom., cov: 33)

Exomes 𝑓: 0.077 ( 4733 hom. )

Consequence

CIITA
NM_000246.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -2.09

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

MHC class II deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

CIITA links:

ENSG00000308110 (HGNC:):

ENSG00000308110 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027588606).

BP6

Variant 16-10907837-T-C is Benign according to our data. Variant chr16-10907837-T-C is described in ClinVar as [Benign]. Clinvar id is 317709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4 link	c.2345T>C	p.Val782Ala	missense_variant	Exon 11 of 20	ENST00000324288.14	NP_000237.2	P33076A0A0B4J1S1Q66X48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14 link	c.2345T>C	p.Val782Ala	missense_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8		A0A0B4J1S1

Frequencies

GnomAD3 genomes

AF:

0.0622

AC:

9464

AN:

152094

Hom.:

366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0351

Gnomad AMI

AF:

0.126

Gnomad AMR

AF:

0.0556

Gnomad ASJ

AF:

0.0611

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0478

Gnomad FIN

AF:

0.0730

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0827

Gnomad OTH

AF:

0.0808

GnomAD2 exomes

AF:

0.0629

AC:

15563

AN:

247422

AF XY:

0.0650

show subpopulations

Gnomad AFR exome

AF:

0.0343

Gnomad AMR exome

AF:

0.0376

Gnomad ASJ exome

AF:

0.0638

Gnomad EAS exome

AF:

0.000607

Gnomad FIN exome

AF:

0.0722

Gnomad NFE exome

AF:

0.0851

Gnomad OTH exome

AF:

0.0721

GnomAD4 exome

AF:

0.0773

AC:

112944

AN:

1461252

Hom.:

4733

Cov.:

AF XY:

0.0775

AC XY:

56362

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.0362

AC:

1211

AN:

33450

American (AMR)

AF:

0.0401

AC:

1791

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.0608

AC:

1584

AN:

26070

East Asian (EAS)

AF:

0.000756

AC:

AN:

39692

South Asian (SAS)

AF:

0.0544

AC:

4689

AN:

86224

European-Finnish (FIN)

AF:

0.0730

AC:

3890

AN:

53262

Middle Eastern (MID)

AF:

0.0973

AC:

561

AN:

5764

European-Non Finnish (NFE)

AF:

0.0851

AC:

94578

AN:

1111740

Other (OTH)

AF:

0.0764

AC:

4610

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

6741

13482

20222

26963

33704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0623

AC:

9476

AN:

152212

Hom.:

366

Cov.:

AF XY:

0.0618

AC XY:

4603

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0354

AC:

1470

AN:

41548

American (AMR)

AF:

0.0555

AC:

848

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0611

AC:

212

AN:

3470

East Asian (EAS)

AF:

0.000968

AC:

AN:

5164

South Asian (SAS)

AF:

0.0478

AC:

231

AN:

4828

European-Finnish (FIN)

AF:

0.0730

AC:

774

AN:

10602

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0827

AC:

5620

AN:

67988

Other (OTH)

AF:

0.0799

AC:

169

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

485

970

1456

1941

2426

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0755

Hom.:

967

Bravo

AF:

0.0609

TwinsUK

AF:

0.0809

AC:

300

ALSPAC

AF:

0.0848

AC:

327

ESP6500AA

AF:

0.0364

AC:

159

ESP6500EA

AF:

0.0835

AC:

717

ExAC

AF:

0.0629

AC:

7630

EpiCase

AF:

0.0865

EpiControl

AF:

0.0891

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

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

- -

Jan 13, 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. -

not specified

Benign:1

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 -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.0050

(source)

DANN

Benign

0.46

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.35

T;T

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-1.0

PhyloP100

-2.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.97

.;N

REVEL

Benign

0.20

Sift

Benign

0.59

.;T

Sift4G

Benign

1.0

T;T

Vest4

0.025

MPC

0.15

ClinPred

0.0035

GERP RS

-6.0

gMVP

0.16

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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16-10907837-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over