1-151343848-C-T

Variant names:

• chr1-151343848-C-T
• rs2233851
• NM_001025603.2:c.590G>A

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.590G>A​(p.Arg197Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,614,078 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (2 hom., cov: 32)
  • Exomes 𝑓: 0.010 (86 hom.)
• Consequence: RFX5 NM_001025603.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 3.63
• Publications: 11 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=0.004905492).
• BP6: Variant 1-151343848-C-T is Benign according to our data. Variant chr1-151343848-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 292617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0085 (1294/152308) while in subpopulation AMR AF = 0.0158 (241/15300). AF 95% confidence interval is 0.0141. There are 2 homozygotes in GnomAd4. There are 608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.590G>A	p.Arg197Gln	missense	Exon 9 of 11	NP_001020774.1
	RFX5	NM_000449.4		c.590G>A	p.Arg197Gln	missense	Exon 9 of 11	NP_000440.1
	RFX5	NM_001379412.1		c.590G>A	p.Arg197Gln	missense	Exon 9 of 11	NP_001366341.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RFX5	ENST00000452671.7	TSL:1 MANE Select	c.590G>A	p.Arg197Gln	missense	Exon 9 of 11	ENSP00000389130.2
	RFX5	ENST00000290524.8	TSL:1	c.590G>A	p.Arg197Gln	missense	Exon 9 of 11	ENSP00000290524.4
	RFX5	ENST00000368870.6	TSL:5	c.590G>A	p.Arg197Gln	missense	Exon 9 of 11	ENSP00000357864.2

Frequencies

GnomAD3 genomes AF: 0.00852 AC: 1296 AN: 152190 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.00886 AC: 2224 AN: 251136 AF XY: 0.00901

Gnomad AFR exome AF: 0.00173

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.00984

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00651

Gnomad NFE exome AF: 0.0125

Gnomad OTH exome AF: 0.0126

GnomAD4 exome AF: 0.0102 AC: 14976 AN: 1461770 Hom.: 86 Cov.: 37 AF XY: 0.0101 AC XY: 7368 AN XY: 727174

African (AFR) AF: 0.00266 AC: 89 AN: 33478

American (AMR) AF: 0.0124 AC: 555 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00918 AC: 240 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00155 AC: 134 AN: 86252

European-Finnish (FIN) AF: 0.00818 AC: 437 AN: 53398

Middle Eastern (MID) AF: 0.0146 AC: 83 AN: 5704

European-Non Finnish (NFE) AF: 0.0115 AC: 12792 AN: 1111998

Other (OTH) AF: 0.0107 AC: 644 AN: 60380

GnomAD4 genome AF: 0.00850 AC: 1294 AN: 152308 Hom.: 2 Cov.: 32 AF XY: 0.00816 AC XY: 608 AN XY: 74472

African (AFR) AF: 0.00207 AC: 86 AN: 41560

American (AMR) AF: 0.0158 AC: 241 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0120 AC: 819 AN: 68024

Other (OTH) AF: 0.0180 AC: 38 AN: 2116

Alfa AF: 0.0122 Hom.: 58

Bravo AF: 0.00947

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.00877 AC: 1065

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0143

EpiControl AF: 0.0161

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.078	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.091
Sift	Benign	0.082	T
Sift4G	Benign	0.084	T
Polyphen		0.99	D
Vest4		0.096
MVP		0.79
MPC		0.59
ClinPred		0.029	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.038
gMVP		0.24
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2233851; hg19: chr1-151316324;