rs58873298

Positions:

• chr4-150436867-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001364905.1(LRBA):​c.6781-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,612,926 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (152 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (152 hom.)
• Consequence: LRBA NM_001364905.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.3400
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.32

Genes affected

LRBA (HGNC:1742): (LPS responsive beige-like anchor protein) The protein encoded by this gene is a member of the WDL-BEACH-WD (WBW) gene family. Its expression is induced in B cells and macrophages by bacterial lipopolysaccharides (LPS). The encoded protein associates with protein kinase A and may be involved in leading intracellular vesicles to activated receptor complexes, which aids in the secretion and/or membrane deposition of immune effector molecules. Defects in this gene are associated with the disorder common variable immunodeficiency-8 with autoimmunity. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-150436867-G-A is Benign according to our data. Variant chr4-150436867-G-A is described in ClinVar as [Benign]. Clinvar id is 473183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.6781-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.6781-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes AF: 0.0240 AC: 3646 AN: 152030 Hom.: 151 Cov.: 32

Gnomad AFR AF: 0.0815

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0108

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.00374

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00686 AC: 1716 AN: 250128 Hom.: 65 AF XY: 0.00554 AC XY: 749 AN XY: 135172

Gnomad AFR exome AF: 0.0828

Gnomad AMR exome AF: 0.00397

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000980

Gnomad SAS exome AF: 0.00460

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000495

Gnomad OTH exome AF: 0.00410

GnomAD4 exome AF: 0.00293 AC: 4281 AN: 1460778 Hom.: 152 Cov.: 31 AF XY: 0.00278 AC XY: 2019 AN XY: 726736

Gnomad4 AFR exome AF: 0.0850

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00151

Gnomad4 SAS exome AF: 0.00418

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000352

Gnomad4 OTH exome AF: 0.00626

GnomAD4 genome AF: 0.0240 AC: 3653 AN: 152148 Hom.: 152 Cov.: 32 AF XY: 0.0233 AC XY: 1731 AN XY: 74376

Gnomad4 AFR AF: 0.0815

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00213

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0117 Hom.: 31

Bravo AF: 0.0272

Asia WGS AF: 0.0120 AC: 42 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.34
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.14		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: rs58873298; hg19: chr4-151358019;