1-151341942-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001025603.2(RFX5):c.*244A>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 0.0334 in 696,516 control chromosomes in the GnomAD database, including 537 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (113 hom., cov: 32)
  • Exomes 𝑓: 0.034 (424 hom.)
• Consequence: RFX5 NM_001025603.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.512

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=-0.56).
• BP6: Variant 1-151341942-T-C is Benign according to our data. Variant chr1-151341942-T-C is described in ClinVar as [Benign]. Clinvar id is 292606.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.03 (4571/152180) while in subpopulation NFE AF= 0.0494 (3358/67994). AF 95% confidence interval is 0.048. There are 113 homozygotes in gnomad4. There are 2105 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 113 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX5	NM_001025603.2	c.*244A>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.*244A>G		3_prime_UTR_variant	11/11	1	NM_001025603.2	P1
	ENST00000422153.1	n.334T>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4571 AN: 152062 Hom.: 113 Cov.: 32

Gnomad AFR AF: 0.00930

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00579

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0494

Gnomad OTH AF: 0.0215

GnomAD4 exome AF: 0.0344 AC: 18699 AN: 544336 Hom.: 424 Cov.: 4 AF XY: 0.0327 AC XY: 9615 AN XY: 294182

Gnomad4 AFR exome AF: 0.00868

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.0118

Gnomad4 EAS exome AF: 0.0000668

Gnomad4 SAS exome AF: 0.00581

Gnomad4 FIN exome AF: 0.0424

Gnomad4 NFE exome AF: 0.0483

Gnomad4 OTH exome AF: 0.0313

GnomAD4 genome AF: 0.0300 AC: 4571 AN: 152180 Hom.: 113 Cov.: 32 AF XY: 0.0283 AC XY: 2105 AN XY: 74408

Gnomad4 AFR AF: 0.00927

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.0494

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0351 Hom.: 52

Bravo AF: 0.0275

Asia WGS AF: 0.00549 AC: 20 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	-0.56
Cadd	Benign	9.4
Dann	Benign	0.85
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: rs2233857; hg19: chr1-151314418;