rs4774

Variant names:

• chr16-10906991-G-C
• rs4774
• NM_000246.4:c.1499G>C

Your query was ambiguous. Multiple possible variants found:

• chr16-10906991-G-C
• chr16-10906991-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000246.4(CIITA):​c.1499G>C​(p.Gly500Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,610,818 control chromosomes in the GnomAD database, including 68,025 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G500S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.28 (6096 hom., cov: 32)
  • Exomes 𝑓: 0.29 (61929 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.811
• Publications: 72 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012209415).
• BP6: Variant 16-10906991-G-C is Benign according to our data. Variant chr16-10906991-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 317694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.355 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.1499G>C	p.Gly500Ala	missense	Exon 11 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.1502G>C	p.Gly501Ala	missense	Exon 11 of 20	NP_001273331.1	A0A087X2I7
	CIITA	NM_001379332.1		c.1502G>C	p.Gly501Ala	missense	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.1499G>C	p.Gly500Ala	missense	Exon 11 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.860-1992G>C		intron	N/A	ENSP00000371257.5	P33076-3
	CIITA	ENST00000573309.5	TSL:1	n.1470G>C		non_coding_transcript_exon	Exon 10 of 10

Frequencies

GnomAD3 genomes AF: 0.278 AC: 42294 AN: 151962 Hom.: 6082 Cov.: 32

Gnomad AFR AF: 0.257

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.157

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.230

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.258

GnomAD2 exomes AF: 0.297 AC: 73478 AN: 247744 AF XY: 0.289

Gnomad AFR exome AF: 0.261

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.287

Gnomad EAS exome AF: 0.147

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.288 AC: 419593 AN: 1458738 Hom.: 61929 Cov.: 65 AF XY: 0.286 AC XY: 207725 AN XY: 725854

African (AFR) AF: 0.257 AC: 8612 AN: 33476

American (AMR) AF: 0.461 AC: 20606 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7405 AN: 26134

East Asian (EAS) AF: 0.206 AC: 8181 AN: 39700

South Asian (SAS) AF: 0.259 AC: 22342 AN: 86258

European-Finnish (FIN) AF: 0.244 AC: 12273 AN: 50314

Middle Eastern (MID) AF: 0.250 AC: 1444 AN: 5768

European-Non Finnish (NFE) AF: 0.289 AC: 321378 AN: 1111984

Other (OTH) AF: 0.287 AC: 17352 AN: 60380

GnomAD4 genome AF: 0.278 AC: 42344 AN: 152080 Hom.: 6096 Cov.: 32 AF XY: 0.279 AC XY: 20713 AN XY: 74334

African (AFR) AF: 0.258 AC: 10689 AN: 41506

American (AMR) AF: 0.363 AC: 5547 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 951 AN: 3468

East Asian (EAS) AF: 0.157 AC: 808 AN: 5146

South Asian (SAS) AF: 0.249 AC: 1202 AN: 4828

European-Finnish (FIN) AF: 0.230 AC: 2431 AN: 10578

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.292 AC: 19818 AN: 67954

Other (OTH) AF: 0.261 AC: 550 AN: 2106

Alfa AF: 0.288 Hom.: 4746

Bravo AF: 0.289

TwinsUK AF: 0.288 AC: 1069

ALSPAC AF: 0.286 AC: 1101

ESP6500AA AF: 0.257 AC: 1130

ESP6500EA AF: 0.292 AC: 2514

ExAC AF: 0.290 AC: 35238

Asia WGS AF: 0.266 AC: 924 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.282

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	MHC class II deficiency (4)
-	-	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	4.7
DANN	Benign	0.18
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-0.97	T
PhyloP100		0.81
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.26
Sift	Benign	0.84	T
Sift4G	Benign	1.0	T
Vest4		0.29
MPC		0.14
ClinPred		0.0077	T
GERP RS		-0.80
gMVP		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4774; hg19: chr16-11000848; COSMIC: COSV60853796; COSMIC: COSV60853796;