rs138131380

Variant names:

• chr1-151342628-C-T
• rs138131380
• NM_001025603.2:c.1409G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001025603.2(RFX5):​c.1409G>A​(p.Arg470Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.66
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21614718).

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.1409G>A	p.Arg470Gln	missense	Exon 11 of 11	NP_001020774.1	P48382-1
	RFX5	NM_000449.4		c.1409G>A	p.Arg470Gln	missense	Exon 11 of 11	NP_000440.1	P48382-1
	RFX5	NM_001379412.1		c.1409G>A	p.Arg470Gln	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.1409G>A	p.Arg470Gln	missense	Exon 11 of 11	ENSP00000389130.2	P48382-1
	RFX5	ENST00000290524.8	TSL:1	c.1409G>A	p.Arg470Gln	missense	Exon 11 of 11	ENSP00000290524.4	P48382-1
	RFX5	ENST00000368870.6	TSL:5	c.1409G>A	p.Arg470Gln	missense	Exon 11 of 11	ENSP00000357864.2	P48382-1

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000123 AC: 31 AN: 251476 AF XY: 0.000125

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000121 AC: 177 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.000109 AC XY: 79 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000156 AC: 174 AN: 1112012

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74432

African (AFR) AF: 0.0000963 AC: 4 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.65
MPC		0.66
ClinPred		0.31	T
GERP RS		5.4
Varity_R		0.39
gMVP		0.29
Mutation Taster		=72/28	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: rs138131380; hg19: chr1-151315104;