rs137853099

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The ENST00000452671.7(RFX5):​c.446G>A​(p.Arg149Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RFX5
ENST00000452671.7 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 7.25
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.984

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RFX5NM_001025603.2 linkuse as main transcriptc.446G>A p.Arg149Gln missense_variant 7/11 ENST00000452671.7 NP_001020774.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RFX5ENST00000452671.7 linkuse as main transcriptc.446G>A p.Arg149Gln missense_variant 7/111 NM_001025603.2 ENSP00000389130 P1P48382-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251442
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461890
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

MHC class II deficiency 5 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMNov 01, 2002- -
MHC class II deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 27, 2018This sequence change replaces arginine with glutamine at codon 149 of the RFX5 protein (p.Arg149Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with bare lymphocyte syndrome (BLS) (PMID: 12368908). ClinVar contains an entry for this variant (Variation ID: 7648). Experimental studies using a patient-derived cell line have shown that this missense change abolishes RFX5 DNA binding activity and silences the expression of MHC class II genes (PMID: 12368908). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.47
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D;D;.;D;D;T;D;D
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.97
.;.;D;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
3.5
M;M;.;M;.;.;.;.
MutationTaster
Benign
1.0
A;A;A;A
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.8
D;D;D;D;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;.;.;.;.
Polyphen
1.0
D;D;.;D;.;.;.;.
Vest4
0.88
MutPred
0.98
Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);.;Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);Loss of MoRF binding (P = 0.0329);
MVP
0.95
MPC
0.67
ClinPred
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.90
gMVP
0.72

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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.

Other links and lift over

dbSNP: rs137853099; hg19: chr1-151316920; COSMIC: COSV100923880; COSMIC: COSV100923880; API