19-19201687-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003721.4(RFXANK):c.751C>G(p.Gln251Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0067 in 1,614,100 control chromosomes in the GnomAD database, including 837 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0076 ( 79 hom., cov: 32)

Exomes 𝑓: 0.0066 ( 758 hom. )

Consequence

RFXANK
NM_003721.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.54

Publications

13 publications found

Variant links:

Genes affected

RFXANK (HGNC:9987): (regulatory factor X associated ankyrin containing protein) Major histocompatibility (MHC) class II molecules are transmembrane proteins that have a central role in development and control of the immune system. The protein encoded by this gene, along with regulatory factor X-associated protein and regulatory factor-5, forms a complex that binds to the X box motif of certain MHC class II gene promoters and activates their transcription. Once bound to the promoter, this complex associates with the non-DNA-binding factor MHC class II transactivator, which controls the cell type specificity and inducibility of MHC class II gene expression. This protein contains ankyrin repeats involved in protein-protein interactions. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group B. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2013]

RFXANK links:

NR2C2AP (HGNC:30763): (nuclear receptor 2C2 associated protein) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NR2C2AP 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 (MetaRNN=0.0014945269).

BP6

Variant 19-19201687-C-G is Benign according to our data. Variant chr19-19201687-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 328648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003721.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RFXANK	NM_003721.4	MANE Select	c.751C>G	p.Gln251Glu	missense	Exon 10 of 10	NP_003712.1
NR2C2AP	NM_176880.6	MANE Select	c.*238G>C		3_prime_UTR	Exon 5 of 5	NP_795361.1
RFXANK	NM_001370238.1		c.826C>G	p.Gln276Glu	missense	Exon 10 of 10	NP_001357167.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RFXANK	ENST00000303088.9	TSL:1 MANE Select	c.751C>G	p.Gln251Glu	missense	Exon 10 of 10	ENSP00000305071.2
RFXANK	ENST00000407360.7	TSL:1	c.751C>G	p.Gln251Glu	missense	Exon 9 of 9	ENSP00000384572.3
RFXANK	ENST00000456252.7	TSL:1	c.685C>G	p.Gln229Glu	missense	Exon 9 of 9	ENSP00000409138.2

Frequencies

GnomAD3 genomes

AF:

0.00758

AC:

1153

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00140

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00116

Gnomad EAS

AF:

0.174

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00499

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.0149

AC:

3728

AN:

251010

AF XY:

0.0135

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.177

Gnomad FIN exome

AF:

0.00450

Gnomad NFE exome

AF:

0.00158

Gnomad OTH exome

AF:

0.00603

GnomAD4 exome

AF:

0.00661

AC:

9659

AN:

1461800

Hom.:

758

Cov.:

AF XY:

0.00640

AC XY:

4655

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.000470

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000574

AC:

AN:

26134

East Asian (EAS)

AF:

0.189

AC:

7522

AN:

39700

South Asian (SAS)

AF:

0.00394

AC:

340

AN:

86254

European-Finnish (FIN)

AF:

0.00551

AC:

294

AN:

53352

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000661

AC:

735

AN:

1111996

Other (OTH)

AF:

0.0118

AC:

714

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

600

1200

1801

2401

3001

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<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:

0.00757

AC:

1153

AN:

152300

Hom.:

Cov.:

AF XY:

0.00833

AC XY:

620

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00140

AC:

AN:

41570

American (AMR)

AF:

0.00124

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00116

AC:

AN:

3462

East Asian (EAS)

AF:

0.175

AC:

901

AN:

5162

South Asian (SAS)

AF:

0.00621

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00499

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00115

AC:

AN:

68034

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

111

167

222

278

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:

0.00657

Hom.:

Bravo

AF:

0.00780

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0143

AC:

1733

Asia WGS

AF:

0.0770

AC:

268

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000711

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

MHC class II deficiency (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.093

Eigen

Benign

-0.16

Eigen_PC

Benign

0.026

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0015

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

PhyloP100

3.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.83

REVEL

Benign

0.050

Sift

Uncertain

0.029

Sift4G

Uncertain

0.054

Polyphen

0.0010

Vest4

0.22

MPC

0.27

ClinPred

0.0094

GERP RS

4.8

Varity_R

0.22

gMVP

0.22

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over