NM_000246.4:c.2342C>T

Variant names:

• chr16-10907834-C-T
• rs13330686
• NM_000246.4:c.2342C>T

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.2342C>T​(p.Ser781Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 1,613,572 control chromosomes in the GnomAD database, including 5,076 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S781W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.062 (364 hom., cov: 33)
  • Exomes 𝑓: 0.077 (4712 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.770
• Publications: 17 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=0.0021781623).
• BP6: Variant 16-10907834-C-T is Benign according to our data. Variant chr16-10907834-C-T is described in ClinVar as Benign. ClinVar VariationId is 317708.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0807 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.2342C>T	p.Ser781Leu	missense	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2345C>T	p.Ser782Leu	missense	Exon 11 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.2345C>T	p.Ser782Leu	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.2342C>T	p.Ser781Leu	missense	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.860-1149C>T		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000573309.5	TSL:1	n.2313C>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.0621 AC: 9454 AN: 152202 Hom.: 364 Cov.: 33

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.0555

Gnomad ASJ AF: 0.0611

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.0478

Gnomad FIN AF: 0.0729

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0825

Gnomad OTH AF: 0.0807

GnomAD2 exomes AF: 0.0628 AC: 15538 AN: 247378 AF XY: 0.0649

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.0376

Gnomad ASJ exome AF: 0.0636

Gnomad EAS exome AF: 0.000607

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.0850

Gnomad OTH exome AF: 0.0722

GnomAD4 exome AF: 0.0771 AC: 112696 AN: 1461252 Hom.: 4712 Cov.: 70 AF XY: 0.0774 AC XY: 56241 AN XY: 726918

African (AFR) AF: 0.0362 AC: 1211 AN: 33454

American (AMR) AF: 0.0400 AC: 1789 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1584 AN: 26068

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39692

South Asian (SAS) AF: 0.0543 AC: 4686 AN: 86222

European-Finnish (FIN) AF: 0.0730 AC: 3890 AN: 53262

Middle Eastern (MID) AF: 0.0970 AC: 559 AN: 5762

European-Non Finnish (NFE) AF: 0.0849 AC: 94340 AN: 1111736

Other (OTH) AF: 0.0763 AC: 4607 AN: 60380

GnomAD4 genome AF: 0.0621 AC: 9466 AN: 152320 Hom.: 364 Cov.: 33 AF XY: 0.0618 AC XY: 4601 AN XY: 74484

African (AFR) AF: 0.0354 AC: 1471 AN: 41586

American (AMR) AF: 0.0554 AC: 848 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0611 AC: 212 AN: 3472

East Asian (EAS) AF: 0.000966 AC: 5 AN: 5178

South Asian (SAS) AF: 0.0478 AC: 231 AN: 4830

European-Finnish (FIN) AF: 0.0729 AC: 773 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0825 AC: 5610 AN: 68014

Other (OTH) AF: 0.0799 AC: 169 AN: 2116

Alfa AF: 0.0610 Hom.: 203

Bravo AF: 0.0609

TwinsUK AF: 0.0806 AC: 299

ALSPAC AF: 0.0854 AC: 329

ESP6500AA AF: 0.0363 AC: 159

ESP6500EA AF: 0.0821 AC: 705

ExAC AF: 0.0629 AC: 7620

Asia WGS AF: 0.0300 AC: 104 AN: 3478

EpiCase AF: 0.0864

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	0.066
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.29
DANN	Benign	0.40
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.32	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.97	T
PhyloP100		-0.77
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.13
Sift	Benign	0.68	T
Sift4G	Benign	0.64	T
Vest4		0.038
MPC		0.11
ClinPred		0.0047	T
GERP RS		-7.7
gMVP		0.17
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: rs13330686; hg19: chr16-11001691; COSMIC: COSV60855363;