16-10907913-G-T

Variant names:

• chr16-10907913-G-T
• rs34654419
• NM_000246.4:c.2421G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000246.4(CIITA):​c.2421G>T​(p.Leu807Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,577,540 control chromosomes in the GnomAD database, including 37,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L807L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (3672 hom., cov: 33)
  • Exomes 𝑓: 0.21 (33595 hom.)
• Consequence: CIITA NM_000246.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 0.737
• Publications: 17 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000308110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-10907913-G-T is Benign according to our data. Variant chr16-10907913-G-T is described in ClinVar as Benign. ClinVar VariationId is 317712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.737 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000246.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	NM_000246.4	MANE Select	c.2421G>T	p.Leu807Leu	synonymous	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2424G>T	p.Leu808Leu	synonymous	Exon 11 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.2424G>T	p.Leu808Leu	synonymous	Exon 11 of 20	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2421G>T	p.Leu807Leu	synonymous	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.860-1070G>T		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000573309.5	TSL:1	n.2392G>T		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32380 AN: 152106 Hom.: 3659 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.154

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.206

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.235 AC: 50851 AN: 216436 AF XY: 0.225

Gnomad AFR exome AF: 0.205

Gnomad AMR exome AF: 0.445

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.210

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.211 AC: 300723 AN: 1425316 Hom.: 33595 Cov.: 63 AF XY: 0.209 AC XY: 147769 AN XY: 705370

African (AFR) AF: 0.199 AC: 6415 AN: 32266

American (AMR) AF: 0.427 AC: 17187 AN: 40214

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5354 AN: 23474

East Asian (EAS) AF: 0.204 AC: 8043 AN: 39394

South Asian (SAS) AF: 0.203 AC: 16216 AN: 79782

European-Finnish (FIN) AF: 0.166 AC: 8562 AN: 51450

Middle Eastern (MID) AF: 0.182 AC: 1010 AN: 5560

European-Non Finnish (NFE) AF: 0.206 AC: 225249 AN: 1094540

Other (OTH) AF: 0.216 AC: 12687 AN: 58636

GnomAD4 genome AF: 0.213 AC: 32425 AN: 152224 Hom.: 3672 Cov.: 33 AF XY: 0.213 AC XY: 15876 AN XY: 74426

African (AFR) AF: 0.203 AC: 8445 AN: 41546

American (AMR) AF: 0.316 AC: 4835 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 765 AN: 3472

East Asian (EAS) AF: 0.154 AC: 795 AN: 5152

South Asian (SAS) AF: 0.203 AC: 980 AN: 4828

European-Finnish (FIN) AF: 0.152 AC: 1616 AN: 10622

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.211 AC: 14364 AN: 67984

Other (OTH) AF: 0.193 AC: 409 AN: 2114

Alfa AF: 0.217 Hom.: 1019

Bravo AF: 0.225

Asia WGS AF: 0.235 AC: 817 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	MHC class II deficiency (4)
-	-	1	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.2
DANN	Benign	0.72
PhyloP100		0.74
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34654419; hg19: chr16-11001770; COSMIC: COSV60854299;