rs2233843

Variant names:

• chr1-151346257-C-T
• rs2233843
• NM_001025603.2:c.64G>A

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.64G>A​(p.Ala22Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,614,166 control chromosomes in the GnomAD database, including 133 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 0.016 (71 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (62 hom.)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.159
• 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=0.0016357601).
• BP6: Variant 1-151346257-C-T is Benign according to our data. Variant chr1-151346257-C-T is described in ClinVar as Benign. ClinVar VariationId is 292618.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0523 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	NM_001025603.2	MANE Select	c.64G>A	p.Ala22Thr	missense	Exon 3 of 11	NP_001020774.1	P48382-1
	RFX5	NM_000449.4		c.64G>A	p.Ala22Thr	missense	Exon 3 of 11	NP_000440.1	P48382-1
	RFX5	NM_001379412.1		c.64G>A	p.Ala22Thr	missense	Exon 3 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.64G>A	p.Ala22Thr	missense	Exon 3 of 11	ENSP00000389130.2	P48382-1
	RFX5	ENST00000290524.8	TSL:1	c.64G>A	p.Ala22Thr	missense	Exon 3 of 11	ENSP00000290524.4	P48382-1
	RFX5	ENST00000479681.5	TSL:1	n.297G>A		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2364 AN: 152160 Hom.: 71 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00497

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00425 AC: 1068 AN: 251466 AF XY: 0.00329

Gnomad AFR exome AF: 0.0561

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00228

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00180 AC: 2625 AN: 1461888 Hom.: 62 Cov.: 31 AF XY: 0.00157 AC XY: 1142 AN XY: 727244

African (AFR) AF: 0.0596 AC: 1994 AN: 33478

American (AMR) AF: 0.00297 AC: 133 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00310 AC: 81 AN: 26136

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

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.000128 AC: 142 AN: 1112012

Other (OTH) AF: 0.00379 AC: 229 AN: 60396

GnomAD4 genome AF: 0.0156 AC: 2368 AN: 152278 Hom.: 71 Cov.: 32 AF XY: 0.0152 AC XY: 1129 AN XY: 74466

African (AFR) AF: 0.0542 AC: 2251 AN: 41548

American (AMR) AF: 0.00497 AC: 76 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68018

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00597 Hom.: 66

Bravo AF: 0.0171

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00515 AC: 625

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	MHC class II deficiency (3)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.67	N
PhyloP100		-0.16
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.021
Sift	Benign	0.21	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.038
MVP		0.55
MPC		0.13
ClinPred		0.0011	T
GERP RS		2.0
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.19
Mutation Taster		=99/1	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: rs2233843; hg19: chr1-151318733;