16-10902050-C-G

Variant names:

• chr16-10902050-C-G
• rs34648899
• NM_000246.4:c.494C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000246.4(CIITA):​c.494C>G​(p.Thr165Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000826 in 1,614,156 control chromosomes in the GnomAD database, including 9 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. T165N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.579
• Publications: 2 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=0.0032983124).
• BP6: Variant 16-10902050-C-G is Benign according to our data. Variant chr16-10902050-C-G is described in ClinVar as Benign. ClinVar VariationId is 459197.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00446 (680/152348) while in subpopulation AFR AF = 0.0152 (632/41584). AF 95% confidence interval is 0.0142. There are 4 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.494C>G	p.Thr165Ser	missense	Exon 7 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.497C>G	p.Thr166Ser	missense	Exon 7 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.497C>G	p.Thr166Ser	missense	Exon 7 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.494C>G	p.Thr165Ser	missense	Exon 7 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.481+492C>G		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000537380.1	TSL:1	n.494C>G		non_coding_transcript_exon	Exon 7 of 11

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 677 AN: 152230 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00124 AC: 311 AN: 251266 AF XY: 0.000869

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000447 AC: 654 AN: 1461808 Hom.: 5 Cov.: 35 AF XY: 0.000403 AC XY: 293 AN XY: 727214

African (AFR) AF: 0.0145 AC: 485 AN: 33476

American (AMR) AF: 0.00143 AC: 64 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1112008

Other (OTH) AF: 0.00132 AC: 80 AN: 60396

GnomAD4 genome AF: 0.00446 AC: 680 AN: 152348 Hom.: 4 Cov.: 32 AF XY: 0.00408 AC XY: 304 AN XY: 74498

African (AFR) AF: 0.0152 AC: 632 AN: 41584

American (AMR) AF: 0.00235 AC: 36 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68044

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.000282 Hom.: 2

Bravo AF: 0.00510

ESP6500AA AF: 0.0121 AC: 53

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00151 AC: 183

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.1
DANN	Benign	0.33
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.58
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.087
Sift	Benign	0.81	T
Sift4G	Benign	0.65	T
Vest4		0.12
MutPred		0.072		Gain of phosphorylation at T165 (P = 0.083)
MVP		0.63
MPC		0.11
ClinPred		0.0028	T
GERP RS		2.1
gMVP		0.11
Mutation Taster		=100/0	polymorphism

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: rs34648899; hg19: chr16-10995907;