rs2233854

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-151342811-G-C
• chr1-151342811-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001025603.2(RFX5):​c.1226C>G​(p.Pro409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,614,066 control chromosomes in the GnomAD database, including 20,506 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P409S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1331 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19175 hom.)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013961494).
• BP6: Variant 1-151342811-G-C is Benign according to our data. Variant chr1-151342811-G-C is described in ClinVar as Benign. ClinVar VariationId is 292612.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

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>G	p.Pro409Arg	missense	Exon 11 of 11	NP_001020774.1
	RFX5	NM_000449.4		c.1226C>G	p.Pro409Arg	missense	Exon 11 of 11	NP_000440.1
	RFX5	NM_001379412.1		c.1226C>G	p.Pro409Arg	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>G	p.Pro409Arg	missense	Exon 11 of 11	ENSP00000389130.2
	RFX5	ENST00000290524.8	TSL:1	c.1226C>G	p.Pro409Arg	missense	Exon 11 of 11	ENSP00000290524.4
	RFX5	ENST00000368870.6	TSL:5	c.1226C>G	p.Pro409Arg	missense	Exon 11 of 11	ENSP00000357864.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17234 AN: 152082 Hom.: 1332 Cov.: 32

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.292

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0867

Gnomad FIN AF: 0.119

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.119

GnomAD2 exomes AF: 0.117 AC: 29456 AN: 251356 AF XY: 0.121

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.0720

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.155 AC: 226399 AN: 1461866 Hom.: 19175 Cov.: 34 AF XY: 0.154 AC XY: 111943 AN XY: 727228

African (AFR) AF: 0.0230 AC: 770 AN: 33480

American (AMR) AF: 0.0737 AC: 3296 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2977 AN: 26132

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39700

South Asian (SAS) AF: 0.101 AC: 8680 AN: 86258

European-Finnish (FIN) AF: 0.128 AC: 6831 AN: 53416

Middle Eastern (MID) AF: 0.0877 AC: 506 AN: 5768

European-Non Finnish (NFE) AF: 0.176 AC: 195174 AN: 1111992

Other (OTH) AF: 0.135 AC: 8153 AN: 60396

GnomAD4 genome AF: 0.113 AC: 17230 AN: 152200 Hom.: 1331 Cov.: 32 AF XY: 0.110 AC XY: 8185 AN XY: 74400

African (AFR) AF: 0.0303 AC: 1259 AN: 41540

American (AMR) AF: 0.113 AC: 1719 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3470

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5188

South Asian (SAS) AF: 0.0874 AC: 422 AN: 4830

European-Finnish (FIN) AF: 0.119 AC: 1258 AN: 10580

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11606 AN: 67994

Other (OTH) AF: 0.117 AC: 247 AN: 2114

Alfa AF: 0.144 Hom.: 1357

Bravo AF: 0.107

TwinsUK AF: 0.176 AC: 651

ALSPAC AF: 0.174 AC: 672

ESP6500AA AF: 0.0350 AC: 154

ESP6500EA AF: 0.162 AC: 1392

ExAC AF: 0.119 AC: 14417

Asia WGS AF: 0.0370 AC: 132 AN: 3478

EpiCase AF: 0.166

EpiControl AF: 0.169

ClinVar

ClinVar submissions as Germline

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.8
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.027
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.66	P
Vest4		0.19
MPC		0.20
ClinPred		0.019	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.064
gMVP		0.21
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV51839208; COSMIC: COSV51839208;