1-151340665-A-AAAT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001025603.2(RFX5):c.*1520_*1521insATT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 152,282 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RFX5 NM_001025603.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00347 (529/152282) while in subpopulation SAS AF= 0.00932 (45/4830). AF 95% confidence interval is 0.00716. There are 3 homozygotes in gnomad4. There are 261 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RFX5	NM_001025603.2	c.*1520_*1521insATT		3_prime_UTR_variant	11/11	ENST00000452671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RFX5	ENST00000452671.7	c.*1520_*1521insATT		3_prime_UTR_variant	11/11	1	NM_001025603.2	P1
RFX5	ENST00000290524.8	c.*1520_*1521insATT		3_prime_UTR_variant	11/11	1		P1
	ENST00000422153.1	n.18_19insAAT		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00529

Gnomad OTH AF: 0.00335

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 434 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 262

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152282 Hom.: 3 Cov.: 32 AF XY: 0.00351 AC XY: 261 AN XY: 74452

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.00529

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00416 Hom.: 0

Bravo AF: 0.00323

Asia WGS AF: 0.00145 AC: 5 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

MHC class II deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs529662057; hg19: chr1-151313141;