rs78108426

chr16-10907564-C-Achr16-10907564-C-T

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.2072C>A(p.Ala691Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,614,164 control chromosomes in the GnomAD database, including 573 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A691V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (58 hom., cov: 33)
  • Exomes 𝑓: 0.013 (515 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.966

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=0.0023306608).
• BP6: Variant 16-10907564-C-A is Benign according to our data. Variant chr16-10907564-C-A is described in ClinVar as [Benign]. Clinvar id is 317702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10907564-C-A is described in Lovd as [Benign]. Variant chr16-10907564-C-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.2072C>A	p.Ala691Asp	missense_variant	11/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.2072C>A	p.Ala691Asp	missense_variant	11/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2588 AN: 152174 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.131

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.00320

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00703

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0223 AC: 5606 AN: 251120 Hom.: 194 AF XY: 0.0221 AC XY: 2999 AN XY: 135824

Gnomad AFR exome AF: 0.0208

Gnomad AMR exome AF: 0.0150

Gnomad ASJ exome AF: 0.0159

Gnomad EAS exome AF: 0.134

Gnomad SAS exome AF: 0.0307

Gnomad FIN exome AF: 0.00601

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.0197

GnomAD4 exome AF: 0.0134 AC: 19573 AN: 1461872 Hom.: 515 Cov.: 70 AF XY: 0.0140 AC XY: 10193 AN XY: 727236

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0163

Gnomad4 EAS exome AF: 0.133

Gnomad4 SAS exome AF: 0.0300

Gnomad4 FIN exome AF: 0.00581

Gnomad4 NFE exome AF: 0.00747

Gnomad4 OTH exome AF: 0.0200

GnomAD4 genome AF: 0.0170 AC: 2583 AN: 152292 Hom.: 58 Cov.: 33 AF XY: 0.0175 AC XY: 1307 AN XY: 74476

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.0176

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.00320

Gnomad4 NFE AF: 0.00701

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.0124 Hom.: 86

Bravo AF: 0.0191

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.0220 AC: 2673

Asia WGS AF: 0.0920 AC: 317 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00848

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

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 -

CIITA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.35	T
Sift4G	Uncertain	0.019	D;D
Vest4		0.54
MPC		0.33
ClinPred		0.0066	T
GERP RS		3.3
gMVP		0.56

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

LitVar

Other links and lift over

dbSNP: rs78108426; hg19: chr16-11001421; COSMIC: COSV60858376; COSMIC: COSV60858376;