16-10922188-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000246.4(CIITA):c.3171C>T(p.Cys1057=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,613,726 control chromosomes in the GnomAD database, including 9,765 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (737 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9028 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.73

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 16-10922188-C-T is Benign according to our data. Variant chr16-10922188-C-T is described in ClinVar as [Benign]. Clinvar id is 317725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.3171C>T	p.Cys1057=	synonymous_variant	17/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.3171C>T	p.Cys1057=	synonymous_variant	17/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14834 AN: 152178 Hom.: 738 Cov.: 33

Gnomad AFR AF: 0.0738

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0968

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.0772

Gnomad FIN AF: 0.0943

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.118

GnomAD3 exomes AF: 0.103 AC: 25921 AN: 251430 Hom.: 1455 AF XY: 0.103 AC XY: 14025 AN XY: 135894

Gnomad AFR exome AF: 0.0748

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0994

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.0847

Gnomad FIN exome AF: 0.0962

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.107

GnomAD4 exome AF: 0.108 AC: 158382 AN: 1461430 Hom.: 9028 Cov.: 33 AF XY: 0.108 AC XY: 78600 AN XY: 727050

Gnomad4 AFR exome AF: 0.0686

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.0965

Gnomad4 EAS exome AF: 0.156

Gnomad4 SAS exome AF: 0.0866

Gnomad4 FIN exome AF: 0.0958

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.0974 AC: 14833 AN: 152296 Hom.: 737 Cov.: 33 AF XY: 0.0973 AC XY: 7249 AN XY: 74468

Gnomad4 AFR AF: 0.0737

Gnomad4 AMR AF: 0.121

Gnomad4 ASJ AF: 0.0968

Gnomad4 EAS AF: 0.168

Gnomad4 SAS AF: 0.0767

Gnomad4 FIN AF: 0.0943

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.117

Alfa AF: 0.104 Hom.: 1320

Bravo AF: 0.102

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.110

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.79
Dann	Benign	0.85

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: rs2229322; hg19: chr16-11016045; COSMIC: COSV60854131; COSMIC: COSV60854131;