16-10877285-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000246.4(CIITA):c.-46G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,594,262 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0091 (33 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (27 hom.)
• Consequence: CIITA NM_000246.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.227

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-10877285-G-A is Benign according to our data. Variant chr16-10877285-G-A is described in ClinVar as [Benign]. Clinvar id is 317673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00906 (1380/152312) while in subpopulation AFR AF= 0.0311 (1294/41554). AF 95% confidence interval is 0.0297. There are 33 homozygotes in gnomad4. There are 671 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.-46G>A		5_prime_UTR_variant	1/20	ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.-46G>A		5_prime_UTR_variant	1/20	1	NM_000246.4	P4
	ENST00000572017.1	n.438+11030C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00903 AC: 1374 AN: 152194 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00224 AC: 520 AN: 232390 Hom.: 9 AF XY: 0.00161 AC XY: 202 AN XY: 125612

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000205

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000175

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00103 AC: 1487 AN: 1441950 Hom.: 27 Cov.: 30 AF XY: 0.000870 AC XY: 624 AN XY: 717250

Gnomad4 AFR exome AF: 0.0316

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.000271

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000142

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000154

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.00906 AC: 1380 AN: 152312 Hom.: 33 Cov.: 32 AF XY: 0.00901 AC XY: 671 AN XY: 74490

Gnomad4 AFR AF: 0.0311

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00311 Hom.: 1

Bravo AF: 0.0103

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.83
Cadd	Benign	11
Dann	Benign	0.93

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: rs115659359; hg19: chr16-10971142;