rs2233851

Positions:

chr1-151343848-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001025603.2(RFX5):c.590G>A(p.Arg197Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,614,078 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 2 hom., cov: 32)

Exomes 𝑓: 0.010 ( 86 hom. )

Consequence

RFX5
NM_001025603.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.63

Variant links:

Genes affected

RFX5 (HGNC:9986): (regulatory factor X5) A lack of MHC-II expression results in a severe immunodeficiency syndrome called MHC-II deficiency, or the bare lymphocyte syndrome (BLS; MIM 209920). At least 4 complementation groups have been identified in B-cell lines established from patients with BLS. The molecular defects in complementation groups B, C, and D all lead to a deficiency in RFX, a nuclear protein complex that binds to the X box of MHC-II promoters. The lack of RFX binding activity in complementation group C results from mutations in the RFX5 gene encoding the 75-kD subunit of RFX (Steimle et al., 1995). RFX5 is the fifth member of the growing family of DNA-binding proteins sharing a novel and highly characteristic DNA-binding domain called the RFX motif. Multiple alternatively spliced transcript variants have been found but the full-length natures of only two have been determined. [provided by RefSeq, Jul 2008]

RFX5 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=0.004905492).

BP6

Variant 1-151343848-C-T is Benign according to our data. Variant chr1-151343848-C-T is described in ClinVar as [Benign]. Clinvar id is 292617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-151343848-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0085 (1294/152308) while in subpopulation AMR AF= 0.0158 (241/15300). AF 95% confidence interval is 0.0141. There are 2 homozygotes in gnomad4. There are 608 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RFX5	NM_001025603.2 linkuse as main transcript	c.590G>A	p.Arg197Gln	missense_variant	9/11	ENST00000452671.7	NP_001020774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RFX5	ENST00000452671.7 linkuse as main transcript	c.590G>A	p.Arg197Gln	missense_variant	9/11	1	NM_001025603.2	ENSP00000389130	P1	P48382-1

Frequencies

GnomAD3 genomes

AF:

0.00852

AC:

1296

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00893

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0121

Gnomad OTH

AF:

0.0181

GnomAD3 exomes

AF:

0.00886

AC:

2224

AN:

251136

Hom.:

AF XY:

0.00901

AC XY:

1223

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.00984

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00651

Gnomad NFE exome

AF:

0.0125

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0102

AC:

14976

AN:

1461770

Hom.:

Cov.:

AF XY:

0.0101

AC XY:

7368

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00266

Gnomad4 AMR exome

AF:

0.0124

Gnomad4 ASJ exome

AF:

0.00918

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.00818

Gnomad4 NFE exome

AF:

0.0115

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00850

AC:

1294

AN:

152308

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

608

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00207

Gnomad4 AMR

AF:

0.0158

Gnomad4 ASJ

AF:

0.00893

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00594

Gnomad4 NFE

AF:

0.0120

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0132

Hom.:

Bravo

AF:

0.00947

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.0126

AC:

108

ExAC

AF:

0.00877

AC:

1065

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0143

EpiControl

AF:

0.0161

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

MHC class II deficiency

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	RFX5: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

RFX5-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.078

T;T;.;T;T;T

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.89

.;.;D;D;D;D

MetaRNN

Benign

0.0049

T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Uncertain

2.5

M;M;.;M;.;.

MutationTaster

Benign

0.60

D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.29

N;N;N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.082

T;T;T;T;T;T

Sift4G

Benign

0.084

T;T;T;T;.;.

Polyphen

0.99

D;D;.;D;.;.

Vest4

0.096

MVP

0.79

MPC

0.59

ClinPred

0.029

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.038

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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