16-10902050-C-G

Position:

• chr16-10902050-C-G

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIITA	NM_000246.4	c.494C>G	p.Thr165Ser	missense_variant	7/20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.494C>G	p.Thr165Ser	missense_variant	7/20	1	NM_000246.4	ENSP00000316328.8

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

GnomAD3 exomes AF: 0.00124 AC: 311 AN: 251266 Hom.: 1 AF XY: 0.000869 AC XY: 118 AN XY: 135818

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00132

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

Gnomad4 AFR AF: 0.0152

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00379

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

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

CIITA-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2020

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). -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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;T;T;T;T
MetaRNN	Benign	0.0033	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.040	.;.;.;N;.
REVEL	Benign	0.087
Sift	Benign	0.81	.;.;.;T;.
Sift4G	Benign	0.65	.;T;T;T;T
Vest4		0.12, 0.087, 0.10
MutPred		0.072		.;.;Gain of phosphorylation at T165 (P = 0.083);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

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: rs34648899; hg19: chr16-10995907;