rs2233855

Variant names:

• chr1-151342542-G-A
• rs2233855
• NM_001025603.2:c.1495C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001025603.2(RFX5):​c.1495C>T​(p.Pro499Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000815 in 1,614,070 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (2 hom.)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.336
• Publications: 5 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033243597).
• BP6: Variant 1-151342542-G-A is Benign according to our data. Variant chr1-151342542-G-A is described in ClinVar as Benign. ClinVar VariationId is 292610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00415 (632/152244) while in subpopulation AFR AF = 0.0146 (605/41534). AF 95% confidence interval is 0.0136. There are 4 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	NM_001025603.2	MANE Select	c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	NP_001020774.1	P48382-1
	RFX5	NM_000449.4		c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	NP_000440.1	P48382-1
	RFX5	NM_001379412.1		c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	NP_001366341.1	P48382-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	ENST00000452671.7	TSL:1 MANE Select	c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	ENSP00000389130.2	P48382-1
	RFX5	ENST00000290524.8	TSL:1	c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	ENSP00000290524.4	P48382-1
	RFX5	ENST00000368870.6	TSL:5	c.1495C>T	p.Pro499Ser	missense	Exon 11 of 11	ENSP00000357864.2	P48382-1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.00117 AC: 294 AN: 251316 AF XY: 0.000847

Gnomad AFR exome AF: 0.0158

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000468 AC: 684 AN: 1461826 Hom.: 2 Cov.: 31 AF XY: 0.000393 AC XY: 286 AN XY: 727200

African (AFR) AF: 0.0165 AC: 554 AN: 33476

American (AMR) AF: 0.000872 AC: 39 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111968

Other (OTH) AF: 0.00121 AC: 73 AN: 60394

GnomAD4 genome AF: 0.00415 AC: 632 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74446

African (AFR) AF: 0.0146 AC: 605 AN: 41534

American (AMR) AF: 0.00111 AC: 17 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2114

Alfa AF: 0.00176 Hom.: 5

Bravo AF: 0.00502

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00130 AC: 158

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class II deficiency (3)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	RFX5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.34
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.043
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.63	T
Polyphen		0.67	P
Vest4		0.032
MVP		0.39
MPC		0.15
ClinPred		0.0055	T
GERP RS		1.1
Varity_R		0.033
gMVP		0.18
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2233855; hg19: chr1-151315018;