rs150205851

chr16-10906921-C-A

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.1429C>A(p.Leu477Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,613,454 control chromosomes in the GnomAD database, including 15 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L477L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (8 hom., cov: 33)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.785

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004653871).
• BP6: Variant 16-10906921-C-A is Benign according to our data. Variant chr16-10906921-C-A is described in ClinVar as [Benign]. Clinvar id is 459192.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 = 0.0045 (686/152318) while in subpopulation AFR AF= 0.0159 (659/41574). AF 95% confidence interval is 0.0148. There are 8 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.1429C>A	p.Leu477Ile	missense_variant	11/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.1429C>A	p.Leu477Ile	missense_variant	11/20	1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.00449 AC: 683 AN: 152200 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00120 AC: 298 AN: 248950 Hom.: 0 AF XY: 0.000821 AC XY: 111 AN XY: 135202

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000498 AC: 727 AN: 1461136 Hom.: 7 Cov.: 31 AF XY: 0.000450 AC XY: 327 AN XY: 726912

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.00114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00450 AC: 686 AN: 152318 Hom.: 8 Cov.: 33 AF XY: 0.00419 AC XY: 312 AN XY: 74488

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.000697 Hom.: 0

Bravo AF: 0.00501

ESP6500AA AF: 0.0128 AC: 56

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00150 AC: 182

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.72	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
Sift4G	Benign	0.33	T;T
Vest4		0.16
MVP		0.76
MPC		0.24
ClinPred		0.012	T
GERP RS		0.55
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150205851; hg19: chr16-11000778;