rs4780334

Positions:

• chr16-10908769-G-A
• chr16-10908769-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000246.4(CIITA):​c.2658-260G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.691 in 605,790 control chromosomes in the GnomAD database, including 146,525 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.66 (33337 hom., cov: 32)
  • Exomes 𝑓: 0.70 (113188 hom.)
• Consequence: CIITA NM_000246.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIITA	NM_000246.4	c.2658-260G>A		intron_variant		ENST00000324288.14	NP_000237.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIITA	ENST00000324288.14	c.2658-260G>A		intron_variant		1	NM_000246.4	ENSP00000316328	P4

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99591 AN: 151886 Hom.: 33335 Cov.: 32

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.700

Gnomad AMR AF: 0.603

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.841

Gnomad SAS AF: 0.742

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.703

Gnomad OTH AF: 0.681

GnomAD4 exome AF: 0.703 AC: 318891 AN: 453786 Hom.: 113188 Cov.: 4 AF XY: 0.706 AC XY: 169344 AN XY: 239752

Gnomad4 AFR exome AF: 0.527

Gnomad4 AMR exome AF: 0.542

Gnomad4 ASJ exome AF: 0.714

Gnomad4 EAS exome AF: 0.784

Gnomad4 SAS exome AF: 0.732

Gnomad4 FIN exome AF: 0.755

Gnomad4 NFE exome AF: 0.705

Gnomad4 OTH exome AF: 0.683

GnomAD4 genome AF: 0.655 AC: 99627 AN: 152004 Hom.: 33337 Cov.: 32 AF XY: 0.658 AC XY: 48863 AN XY: 74304

Gnomad4 AFR AF: 0.526

Gnomad4 AMR AF: 0.602

Gnomad4 ASJ AF: 0.717

Gnomad4 EAS AF: 0.841

Gnomad4 SAS AF: 0.743

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.703

Gnomad4 OTH AF: 0.678

Alfa AF: 0.690 Hom.: 61884

Bravo AF: 0.634

Asia WGS AF: 0.720 AC: 2504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.7
DANN	Benign	0.51

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: rs4780334; hg19: chr16-11002626;