rs34282046

Positions:

chr19-19194090-G-C

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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

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:

RFXANK (HGNC:):

RFXANK links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr19-19194090-G-C is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
RFXANK	NM_003721.4 linkuse as main transcript	c.144G>C	p.Glu48Asp	missense_variant	3/10	ENST00000303088.9	NP_003712.1	O14593-1A0A024R7M1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFXANK	ENST00000303088.9 linkuse as main transcript	c.144G>C	p.Glu48Asp	missense_variant	3/10	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

GnomAD3 exomes

AF:

0.0530

AC:

13332

AN:

251488

Hom.:

477

AF XY:

0.0529

AC XY:

7184

AN XY:

135920

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 SAS exome

AF:

0.0706

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

Gnomad4 AFR exome

AF:

0.0105

Gnomad4 AMR exome

AF:

0.0986

Gnomad4 ASJ exome

AF:

0.0476

Gnomad4 EAS exome

AF:

0.0280

Gnomad4 SAS exome

AF:

0.0709

Gnomad4 FIN exome

AF:

0.0230

Gnomad4 NFE exome

AF:

0.0575

Gnomad4 OTH exome

AF:

0.0561

GnomAD4 genome

AF:

0.0454

AC:

6908

AN:

152224

Hom.:

226

Cov.:

AF XY:

0.0455

AC XY:

3386

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.0908

Gnomad4 ASJ

AF:

0.0599

Gnomad4 EAS

AF:

0.0208

Gnomad4 SAS

AF:

0.0662

Gnomad4 FIN

AF:

0.0208

Gnomad4 NFE

AF:

0.0592

Gnomad4 OTH

AF:

0.0573

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

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -

MHC class II deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

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;.;.;.

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

Varity_R

0.046

gMVP

0.098

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over