16-10877247-C-T

Variant names:

• chr16-10877247-C-T
• rs45519531
• ENST00000573309.5:n.32C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000573309.5(CIITA):​n.32C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00575 in 1,293,166 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0046 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0059 (36 hom.)
• Consequence: CIITA ENST00000573309.5 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0720
• Publications: 3 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000262151 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 16-10877247-C-T is Benign according to our data. Variant chr16-10877247-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 886404.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00456 (694/152216) while in subpopulation AMR AF = 0.00602 (92/15278). AF 95% confidence interval is 0.00549. There are 4 homozygotes in GnomAd4. There are 312 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CIITA	NM_000246.4	c.-84C>T		5_prime_UTR_variant	Exon 1 of 20	ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.-84C>T		5_prime_UTR_variant	Exon 1 of 20	1	NM_000246.4	ENSP00000316328.8

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 694 AN: 152098 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00597

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00591 AC: 6741 AN: 1140950 Hom.: 36 Cov.: 16 AF XY: 0.00592 AC XY: 3415 AN XY: 577304

African (AFR) AF: 0.00270 AC: 72 AN: 26710

American (AMR) AF: 0.00453 AC: 169 AN: 37300

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 430 AN: 23590

East Asian (EAS) AF: 0.00 AC: 0 AN: 35636

South Asian (SAS) AF: 0.00309 AC: 232 AN: 75192

European-Finnish (FIN) AF: 0.00109 AC: 55 AN: 50448

Middle Eastern (MID) AF: 0.0337 AC: 136 AN: 4036

European-Non Finnish (NFE) AF: 0.00628 AC: 5269 AN: 838626

Other (OTH) AF: 0.00765 AC: 378 AN: 49412

GnomAD4 genome AF: 0.00456 AC: 694 AN: 152216 Hom.: 4 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74424

African (AFR) AF: 0.00181 AC: 75 AN: 41534

American (AMR) AF: 0.00602 AC: 92 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00353 AC: 17 AN: 4814

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10606

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00597 AC: 406 AN: 68014

Other (OTH) AF: 0.00993 AC: 21 AN: 2114

Alfa AF: 0.00492 Hom.: 0

Bravo AF: 0.00478

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CIITA: BS1, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

MHC class II deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	8.2
DANN	Benign	0.89
PhyloP100		-0.072
PromoterAI		-0.037	Neutral
Mutation Taster		=297/3	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: rs45519531; hg19: chr16-10971104; COSMIC: COSV60857993; COSMIC: COSV60857993;