rs34282046

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.144G>C(p.Glu48Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,068 control chromosomes in the GnomAD database, including 2,728 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 226 hom., cov: 31)

Exomes 𝑓: 0.056 ( 2502 hom. )

Consequence

RFXANK
NM_003721.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.118

Publications

24 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 Gene-Disease associations (from GenCC):

MHC class II deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

RFXANK 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=0.0015137196).

BP6

Variant 19-19194090-G-C is Benign according to our data. Variant chr19-19194090-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 328640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFXANK	NM_003721.4 link	c.144G>C	p.Glu48Asp	missense_variant	Exon 3 of 10	ENST00000303088.9	NP_003712.1	O14593-1A0A024R7M1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9 link	c.144G>C	p.Glu48Asp	missense_variant	Exon 3 of 10	1	NM_003721.4	ENSP00000305071.2		O14593-1

Frequencies

GnomAD3 genomes

AF:

0.0454

AC:

6898

AN:

152106

Hom.:

219

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0899

Gnomad ASJ

AF:

0.0599

Gnomad EAS

AF:

0.0208

Gnomad SAS

AF:

0.0663

Gnomad FIN

AF:

0.0208

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0592

Gnomad OTH

AF:

0.0579

GnomAD2 exomes

AF:

0.0530

AC:

13332

AN:

251488

AF XY:

0.0529

show subpopulations

Gnomad AFR exome

AF:

0.0114

Gnomad AMR exome

AF:

0.0954

Gnomad ASJ exome

AF:

0.0509

Gnomad EAS exome

AF:

0.0131

Gnomad FIN exome

AF:

0.0208

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0534

GnomAD4 exome

AF:

0.0561

AC:

81975

AN:

1461844

Hom.:

2502

Cov.:

AF XY:

0.0564

AC XY:

41030

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.0105

AC:

352

AN:

33480

American (AMR)

AF:

0.0986

AC:

4409

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0476

AC:

1245

AN:

26136

East Asian (EAS)

AF:

0.0280

AC:

1111

AN:

39700

South Asian (SAS)

AF:

0.0709

AC:

6118

AN:

86258

European-Finnish (FIN)

AF:

0.0230

AC:

1230

AN:

53418

Middle Eastern (MID)

AF:

0.0352

AC:

203

AN:

5768

European-Non Finnish (NFE)

AF:

0.0575

AC:

63920

AN:

1111964

Other (OTH)

AF:

0.0561

AC:

3387

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

4631

9262

13894

18525

23156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0454

AC:

6908

AN:

152224

Hom.:

226

Cov.:

AF XY:

0.0455

AC XY:

3386

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0119

AC:

495

AN:

41544

American (AMR)

AF:

0.0908

AC:

1387

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.0599

AC:

208

AN:

3470

East Asian (EAS)

AF:

0.0208

AC:

108

AN:

5180

South Asian (SAS)

AF:

0.0662

AC:

319

AN:

4822

European-Finnish (FIN)

AF:

0.0208

AC:

221

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0592

AC:

4024

AN:

68000

Other (OTH)

AF:

0.0573

AC:

121

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

341

682

1022

1363

1704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0563

Hom.:

175

Bravo

AF:

0.0489

TwinsUK

AF:

0.0588

AC:

218

ALSPAC

AF:

0.0651

AC:

251

ESP6500AA

AF:

0.00953

AC:

ESP6500EA

AF:

0.0560

AC:

482

ExAC

AF:

0.0506

AC:

6144

Asia WGS

AF:

0.0460

AC:

158

AN:

3478

EpiCase

AF:

0.0599

EpiControl

AF:

0.0582

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported. -

MHC class II deficiency

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.3

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0086

T;T;.;.;T;.;T;.

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.73

T;.;T;T;T;T;T;T

MetaRNN

Benign

0.0015

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

.;N;N;.;N;.;.;.

PhyloP100

-0.12

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.050

N;N;N;.;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.23

T;T;T;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.0

.;B;.;.;B;.;.;.

Vest4

0.084, 0.19, 0.081, 0.21

MutPred

0.098

Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;

MPC

0.23

ClinPred

0.00018

GERP RS

0.43

PromoterAI

-0.0080

Neutral

(source)

Varity_R

0.046

gMVP

0.098

Mutation Taster

=100/0

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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rs34282046

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over