dbSNP rs45474796: CIITA:c.200-10T>C (chr16-10895659-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000246.4(CIITA):c.200-10T>C variant causes a 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 intron

Scores

Splicing: ADA: 0.0006234

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.13

Publications

1 publications found

Variant links:

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

CIITA links:

ENSG00000308110 (HGNC:):

ENSG00000308110 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 317676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CIITA	NM_000246.4	MANE Select	c.200-10T>C	intron	N/A	NP_000237.2
CIITA	NM_001286402.1		c.200-10T>C	intron	N/A	NP_001273331.1	A0A087X2I7
CIITA	NM_001379332.1		c.200-10T>C	intron	N/A	NP_001366261.1	A0A087X2I7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CIITA	ENST00000324288.14	TSL:1 MANE Select	c.200-10T>C	intron	N/A	ENSP00000316328.8
CIITA	ENST00000381835.9	TSL:1	c.200-10T>C	intron	N/A	ENSP00000371257.5	P33076-3
CIITA	ENST00000537380.1	TSL:1	n.200-10T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00609

AC:

926

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00897

AC:

2255

AN:

251456

AF XY:

0.00938

show subpopulations

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 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.:

Cov.:

AF XY:

0.0101

AC XY:

7379

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.0107

AC:

480

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00616

AC:

161

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0203

AC:

1749

AN:

86250

European-Finnish (FIN)

AF:

0.00374

AC:

200

AN:

53414

Middle Eastern (MID)

AF:

0.00485

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00997

AC:

11082

AN:

1111984

Other (OTH)

AF:

0.00873

AC:

527

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

791

1582

2373

3164

3955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

432

864

1296

1728

2160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00611

AC:

931

AN:

152272

Hom.:

Cov.:

AF XY:

0.00637

AC XY:

474

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41550

American (AMR)

AF:

0.00647

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00662

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0139

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00387

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00922

AC:

627

AN:

68012

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00826

Hom.:

Bravo

AF:

0.00601

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MHC class II deficiency (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over