1-151341903-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001025603.2(RFX5):c.*283A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 602,896 control chromosomes in the GnomAD database, including 177,146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.78 (46969 hom., cov: 31)
  • Exomes 𝑓: 0.76 (130177 hom.)
• Consequence: RFX5 NM_001025603.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.79

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-151341903-T-C is Benign according to our data. Variant chr1-151341903-T-C is described in ClinVar as [Benign]. Clinvar id is 292605.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX5	NM_001025603.2	c.*283A>G		3_prime_UTR_variant	11/11	ENST00000452671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX5	ENST00000452671.7	c.*283A>G		3_prime_UTR_variant	11/11	1	NM_001025603.2	P1
RFX5	ENST00000290524.8	c.*283A>G		3_prime_UTR_variant	11/11	1		P1
	ENST00000422153.1	n.295T>C		non_coding_transcript_exon_variant	2/2	3
RFX5	ENST00000368870.6	c.*283A>G		3_prime_UTR_variant	11/11	5		P1

Frequencies

GnomAD3 genomes AF: 0.784 AC: 119050 AN: 151922 Hom.: 46919 Cov.: 31

Gnomad AFR AF: 0.839

Gnomad AMI AF: 0.861

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.698

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.816

GnomAD4 exome AF: 0.757 AC: 341414 AN: 450856 Hom.: 130177 Cov.: 3 AF XY: 0.757 AC XY: 185442 AN XY: 244830

Gnomad4 AFR exome AF: 0.842

Gnomad4 AMR exome AF: 0.757

Gnomad4 ASJ exome AF: 0.851

Gnomad4 EAS exome AF: 0.648

Gnomad4 SAS exome AF: 0.735

Gnomad4 FIN exome AF: 0.657

Gnomad4 NFE exome AF: 0.774

Gnomad4 OTH exome AF: 0.783

GnomAD4 genome AF: 0.784 AC: 119158 AN: 152040 Hom.: 46969 Cov.: 31 AF XY: 0.777 AC XY: 57704 AN XY: 74300

Gnomad4 AFR AF: 0.839

Gnomad4 AMR AF: 0.774

Gnomad4 ASJ AF: 0.853

Gnomad4 EAS AF: 0.697

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.652

Gnomad4 NFE AF: 0.778

Gnomad4 OTH AF: 0.818

Alfa AF: 0.780 Hom.: 39727

Bravo AF: 0.798

Asia WGS AF: 0.761 AC: 2650 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.95
Dann	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1752387; hg19: chr1-151314379; COSMIC: COSV51841510; COSMIC: COSV51841510;