16-10877350-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_000246.4(CIITA):c.20G>A(p.Arg7His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,613,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.934

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02474165).
• BP6: Variant 16-10877350-G-A is Benign according to our data. Variant chr16-10877350-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 661814.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.20G>A	p.Arg7His	missense_variant	1/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.20G>A	p.Arg7His	missense_variant	1/20	1	NM_000246.4	P4
	ENST00000572017.1	n.438+10965C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000100 AC: 25 AN: 249312 Hom.: 0 AF XY: 0.000119 AC XY: 16 AN XY: 134826

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000166 AC: 242 AN: 1461032 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 726782

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000186

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74342

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000993 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

MHC class II deficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 7 of the CIITA protein (p.Arg7His). This variant is present in population databases (rs374703179, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CIITA-related conditions. ClinVar contains an entry for this variant (Variation ID: 661814). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 24, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Benign	0.88
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0063	N
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.025	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
Sift4G	Benign	0.083	T;T;T;T
Vest4		0.075
MVP		0.44
MPC		0.16
ClinPred		0.035	T
GERP RS		-4.7
gMVP		0.12

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: rs374703179; hg19: chr16-10971207; COSMIC: COSV60854342; COSMIC: COSV60854342;