16-10907913-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000246.4(CIITA):c.2421G>T(p.Leu807Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,577,540 control chromosomes in the GnomAD database, including 37,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L807L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.21 ( 3672 hom., cov: 33)

Exomes 𝑓: 0.21 ( 33595 hom. )

Consequence

CIITA
NM_000246.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: 0.737

Publications

17 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 16-10907913-G-T is Benign according to our data. Variant chr16-10907913-G-T is described in ClinVar as Benign. ClinVar VariationId is 317712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.737 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4 link	c.2421G>T	p.Leu807Leu	synonymous_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 link	c.2421G>T	p.Leu807Leu	synonymous_variant	Exon 11 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32380

AN:

152106

Hom.:

3659

Cov.:

show subpopulations

Gnomad AFR

AF:

0.203

Gnomad AMI

AF:

0.174

Gnomad AMR

AF:

0.316

Gnomad ASJ

AF:

0.220

Gnomad EAS

AF:

0.154

Gnomad SAS

AF:

0.204

Gnomad FIN

AF:

0.152

Gnomad MID

AF:

0.206

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.235

AC:

50851

AN:

216436

AF XY:

0.225

show subpopulations

Gnomad AFR exome

AF:

0.205

Gnomad AMR exome

AF:

0.445

Gnomad ASJ exome

AF:

0.233

Gnomad EAS exome

AF:

0.145

Gnomad FIN exome

AF:

0.162

Gnomad NFE exome

AF:

0.210

Gnomad OTH exome

AF:

0.225

GnomAD4 exome

AF:

0.211

AC:

300723

AN:

1425316

Hom.:

33595

Cov.:

AF XY:

0.209

AC XY:

147769

AN XY:

705370

show subpopulations

African (AFR)

AF:

0.199

AC:

6415

AN:

32266

American (AMR)

AF:

0.427

AC:

17187

AN:

40214

Ashkenazi Jewish (ASJ)

AF:

0.228

AC:

5354

AN:

23474

East Asian (EAS)

AF:

0.204

AC:

8043

AN:

39394

South Asian (SAS)

AF:

0.203

AC:

16216

AN:

79782

European-Finnish (FIN)

AF:

0.166

AC:

8562

AN:

51450

Middle Eastern (MID)

AF:

0.182

AC:

1010

AN:

5560

European-Non Finnish (NFE)

AF:

0.206

AC:

225249

AN:

1094540

Other (OTH)

AF:

0.216

AC:

12687

AN:

58636

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16054

32108

48162

64216

80270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8006

16012

24018

32024

40030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.213

AC:

32425

AN:

152224

Hom.:

3672

Cov.:

AF XY:

0.213

AC XY:

15876

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.203

AC:

8445

AN:

41546

American (AMR)

AF:

0.316

AC:

4835

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

765

AN:

3472

East Asian (EAS)

AF:

0.154

AC:

795

AN:

5152

South Asian (SAS)

AF:

0.203

AC:

980

AN:

4828

European-Finnish (FIN)

AF:

0.152

AC:

1616

AN:

10622

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.211

AC:

14364

AN:

67984

Other (OTH)

AF:

0.193

AC:

409

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1336

2671

4007

5342

6678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

342

684

1026

1368

1710

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.217

Hom.:

1019

Bravo

AF:

0.225

Asia WGS

AF:

0.235

AC:

817

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:4

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 provided

Benign:1Other:1

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:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

9.2

(source)

DANN

Benign

0.72

PhyloP100

0.74

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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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