rs45474796

Positions:

• chr16-10895659-T-C

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.200-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00942 in 1,614,120 control chromosomes in the GnomAD database, including 102 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (99 hom.)
• Consequence: CIITA NM_000246.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0006234
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.13

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 (BayesDel_noAF=-0.57).
• BP6: Variant 16-10895659-T-C is Benign according to our data. Variant chr16-10895659-T-C is described in ClinVar as [Benign]. Clinvar id is 317676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-10895659-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00611 (931/152272) while in subpopulation SAS AF= 0.0139 (67/4826). AF 95% confidence interval is 0.0112. There are 3 homozygotes in gnomad4. There are 474 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIITA	NM_000246.4	c.200-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000324288.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIITA	ENST00000324288.14	c.200-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000246.4	P4

Frequencies

GnomAD3 genomes AF: 0.00609 AC: 926 AN: 152154 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00622

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00387

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00922

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00897 AC: 2255 AN: 251456 Hom.: 16 AF XY: 0.00938 AC XY: 1275 AN XY: 135900

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0189

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00926

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00976 AC: 14270 AN: 1461848 Hom.: 99 Cov.: 32 AF XY: 0.0101 AC XY: 7379 AN XY: 727232

Gnomad4 AFR exome AF: 0.00119

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.00616

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0203

Gnomad4 FIN exome AF: 0.00374

Gnomad4 NFE exome AF: 0.00997

Gnomad4 OTH exome AF: 0.00873

GnomAD4 genome AF: 0.00611 AC: 931 AN: 152272 Hom.: 3 Cov.: 32 AF XY: 0.00637 AC XY: 474 AN XY: 74450

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.00647

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.00387

Gnomad4 NFE AF: 0.00922

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00857 Hom.: 3

Bravo AF: 0.00601

Asia WGS AF: 0.00606 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

MHC class II deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.050
SpliceAI score (max)		0.14		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: rs45474796; hg19: chr16-10989516;