1-151342811-G-T

Variant names:

• chr1-151342811-G-T
• rs2233854
• NM_001025603.2:c.1226C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025603.2(RFX5):​c.1226C>A​(p.Pro409His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P409R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 25 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12994114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025603.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	NM_001025603.2	MANE Select	c.1226C>A	p.Pro409His	missense	Exon 11 of 11	NP_001020774.1
	RFX5	NM_000449.4		c.1226C>A	p.Pro409His	missense	Exon 11 of 11	NP_000440.1
	RFX5	NM_001379412.1		c.1226C>A	p.Pro409His	missense	Exon 11 of 11	NP_001366341.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	ENST00000452671.7	TSL:1 MANE Select	c.1226C>A	p.Pro409His	missense	Exon 11 of 11	ENSP00000389130.2
	RFX5	ENST00000290524.8	TSL:1	c.1226C>A	p.Pro409His	missense	Exon 11 of 11	ENSP00000290524.4
	RFX5	ENST00000368870.6	TSL:5	c.1226C>A	p.Pro409His	missense	Exon 11 of 11	ENSP00000357864.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1357

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.074
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.043
Sift	Benign	0.062	T
Sift4G	Benign	0.11	T
Polyphen		0.94	P
Vest4		0.16
MutPred		0.12		Loss of relative solvent accessibility (P = 0.1807)
MVP		0.59
MPC		0.33
ClinPred		0.23	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.21
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2233854; hg19: chr1-151315287;