chr16-10915605-A-G

Variant names:

• chr16-10915605-A-G
• rs140103491
• NM_000246.4:c.2924A>G

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.2924A>G​(p.Lys975Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00317 in 1,613,994 control chromosomes in the GnomAD database, including 180 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (165 hom.)
• Consequence: CIITA NM_000246.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.258
• Publications: 3 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000308110 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020398796).
• BP6: Variant 16-10915605-A-G is Benign according to our data. Variant chr16-10915605-A-G is described in ClinVar as Benign. ClinVar VariationId is 317721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.057 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.2924A>G	p.Lys975Arg	missense	Exon 14 of 20	NP_000237.2
	CIITA	NM_001286402.1		c.2927A>G	p.Lys976Arg	missense	Exon 14 of 20	NP_001273331.1
	CIITA	NM_001379332.1		c.2927A>G	p.Lys976Arg	missense	Exon 14 of 20	NP_001366261.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIITA	ENST00000324288.14	TSL:1 MANE Select	c.2924A>G	p.Lys975Arg	missense	Exon 14 of 20	ENSP00000316328.8
	CIITA	ENST00000381835.9	TSL:1	c.1172A>G	p.Lys391Arg	missense	Exon 12 of 18	ENSP00000371257.5
	CIITA	ENST00000886127.1		c.2927A>G	p.Lys976Arg	missense	Exon 14 of 21	ENSP00000556186.1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152022 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.0628

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00646 AC: 1624 AN: 251456 AF XY: 0.00861

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00328 AC: 4796 AN: 1461854 Hom.: 165 Cov.: 31 AF XY: 0.00469 AC XY: 3409 AN XY: 727226

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39696

South Asian (SAS) AF: 0.0513 AC: 4427 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.000114 AC: 127 AN: 1111998

Other (OTH) AF: 0.00349 AC: 211 AN: 60394

GnomAD4 genome AF: 0.00210 AC: 320 AN: 152140 Hom.: 15 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74392

African (AFR) AF: 0.000169 AC: 7 AN: 41500

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000970 AC: 5 AN: 5156

South Asian (SAS) AF: 0.0628 AC: 303 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67986

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000676 Hom.: 4

Bravo AF: 0.000404

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00742 AC: 901

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class II deficiency (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	14
DANN	Benign	0.96
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.87	T
PhyloP100		0.26
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.034
Sift	Benign	0.16	T
Sift4G	Benign	0.15	T
Vest4		0.27
MVP		0.57
MPC		0.11
ClinPred		0.0063	T
GERP RS		-2.1
gMVP		0.42
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs140103491; hg19: chr16-11009462;