1-151343848-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 Likely 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

Publications

11 publications found

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:

RFX5-AS1 (HGNC:40503): (RFX5 antisense RNA 1)

RFX5-AS1 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=0.004905492).

BP6

Variant 1-151343848-C-T is Benign according to our data. Variant chr1-151343848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX5	NM_001025603.2 link	c.590G>A	p.Arg197Gln	missense_variant	Exon 9 of 11	ENST00000452671.7	NP_001020774.1	P48382-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX5	ENST00000452671.7 link	c.590G>A	p.Arg197Gln	missense_variant	Exon 9 of 11	1	NM_001025603.2	ENSP00000389130.2		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

GnomAD2 exomes

AF:

0.00886

AC:

2224

AN:

251136

AF XY:

0.00901

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 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

African (AFR)

AF:

0.00266

AC:

AN:

33478

American (AMR)

AF:

0.0124

AC:

555

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00918

AC:

240

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00155

AC:

134

AN:

86252

European-Finnish (FIN)

AF:

0.00818

AC:

437

AN:

53398

Middle Eastern (MID)

AF:

0.0146

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0115

AC:

12792

AN:

1111998

Other (OTH)

AF:

0.0107

AC:

644

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

889

1778

2666

3555

4444

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

442

884

1326

1768

2210

<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:

0.00850

AC:

1294

AN:

152308

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

608

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41560

American (AMR)

AF:

0.0158

AC:

241

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00893

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.000621

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00594

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0120

AC:

819

AN:

68024

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

143

214

286

357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0122

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

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 11, 2023

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RFX5: BS1, BS2 -

RFX5-related disorder

Benign:1

Apr 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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;.;.

PhyloP100

3.6

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

Mutation Taster

=94/6

polymorphism

(source)

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

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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