NM_000246.4:c.2345T>C

Variant names:

• chr16-10907837-T-C
• rs13336804
• NM_000246.4:c.2345T>C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.09
• Publications: 20 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308110 (HGNC:):

ACMG classification

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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.2345T>C	p.Val782Ala	missense	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2348T>C	p.Val783Ala	missense	Exon 11 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.2348T>C	p.Val783Ala	missense	Exon 11 of 20	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2345T>C	p.Val782Ala	missense	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.860-1146T>C		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000573309.5	TSL:1	n.2316T>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0622 AC: 9464 AN: 152094 Hom.: 366 Cov.: 33

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

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.: 69 AF XY: 0.0775 AC XY: 56362 AN XY: 726930

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: 30 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

GnomAD4 genome AF: 0.0623 AC: 9476 AN: 152212 Hom.: 366 Cov.: 33 AF XY: 0.0618 AC XY: 4603 AN XY: 74426

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: 5 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: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0827 AC: 5620 AN: 67988

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	MHC class II deficiency (4)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0050
DANN	Benign	0.46
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.20
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Vest4		0.025
MPC		0.15
ClinPred		0.0035	T
GERP RS		-6.0
gMVP		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13336804; hg19: chr16-11001694; COSMIC: COSV60855512;