1-151343848-C-G

Variant names:

• chr1-151343848-C-G
• rs2233851
• NM_001025603.2:c.590G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001025603.2(RFX5):​c.590G>C​(p.Arg197Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R197Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30520862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RFX5	NM_001025603.2	c.590G>C	p.Arg197Pro	missense_variant	Exon 9 of 11	ENST00000452671.7	NP_001020774.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RFX5	ENST00000452671.7	c.590G>C	p.Arg197Pro	missense_variant	Exon 9 of 11	1	NM_001025603.2	ENSP00000389130.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;.;T;T;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.72	.;.;T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.31	T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.5	M;M;.;M;.;.
PhyloP100		3.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.7	N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Uncertain	0.020	D;D;T;D;D;T
Sift4G	Uncertain	0.030	D;D;T;D;.;.
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.35
MutPred		0.28		Gain of catalytic residue at P196 (P = 0.0119);Gain of catalytic residue at P196 (P = 0.0119);.;Gain of catalytic residue at P196 (P = 0.0119);Gain of catalytic residue at P196 (P = 0.0119);Gain of catalytic residue at P196 (P = 0.0119);
MVP		0.84
MPC		0.72
ClinPred		0.89	D
GERP RS		3.9
Varity_R		0.30
gMVP		0.72
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs2233851; hg19: chr1-151316324;