rs78108426

Variant names:

• chr16-10907564-C-A
• rs78108426
• NM_000246.4:c.2072C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-10907564-C-A
• chr16-10907564-C-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.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. 14/19 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. 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:6
• Conservation: PhyloP100: 0.966
• Publications: 19 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=0.0023306608).
• BP6: Variant 16-10907564-C-A is Benign according to our data. Variant chr16-10907564-C-A is described in ClinVar as Benign. ClinVar VariationId is 317702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 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.2072C>A	p.Ala691Asp	missense	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2075C>A	p.Ala692Asp	missense	Exon 11 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.2075C>A	p.Ala692Asp	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.2072C>A	p.Ala691Asp	missense	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.860-1419C>A		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000573309.5	TSL:1	n.2043C>A		non_coding_transcript_exon	Exon 10 of 10

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

GnomAD2 exomes AF: 0.0223 AC: 5606 AN: 251120 AF XY: 0.0221

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 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

African (AFR) AF: 0.0192 AC: 643 AN: 33480

American (AMR) AF: 0.0163 AC: 730 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 426 AN: 26136

East Asian (EAS) AF: 0.133 AC: 5263 AN: 39700

South Asian (SAS) AF: 0.0300 AC: 2590 AN: 86256

European-Finnish (FIN) AF: 0.00581 AC: 310 AN: 53402

Middle Eastern (MID) AF: 0.0175 AC: 101 AN: 5768

European-Non Finnish (NFE) AF: 0.00747 AC: 8303 AN: 1112010

Other (OTH) AF: 0.0200 AC: 1207 AN: 60396

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

African (AFR) AF: 0.0194 AC: 805 AN: 41564

American (AMR) AF: 0.0180 AC: 276 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3470

East Asian (EAS) AF: 0.131 AC: 676 AN: 5164

South Asian (SAS) AF: 0.0336 AC: 162 AN: 4826

European-Finnish (FIN) AF: 0.00320 AC: 34 AN: 10624

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00701 AC: 477 AN: 68020

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.0132 Hom.: 163

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class II deficiency (3)
-	-	1	CIITA-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.92	T
PhyloP100		0.97
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.085
Sift	Benign	0.16	T
Sift4G	Uncertain	0.019	D
Vest4		0.54
MPC		0.33
ClinPred		0.0066	T
GERP RS		3.3
gMVP		0.56
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: rs78108426; hg19: chr16-11001421; COSMIC: COSV60858376; COSMIC: COSV60858376;