rs186080

Positions:

• chr4-150844091-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364905.1(LRBA):​c.4569+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.905 in 1,535,700 control chromosomes in the GnomAD database, including 633,998 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.83 (53770 hom., cov: 30)
  • Exomes 𝑓: 0.91 (580228 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.464

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-150844091-G-A is Benign according to our data. Variant chr4-150844091-G-A is described in ClinVar as [Benign]. Clinvar id is 196133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150844091-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.4569+9C>T		intron_variant		ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.4569+9C>T		intron_variant			NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes AF: 0.832 AC: 126304 AN: 151876 Hom.: 53747 Cov.: 30

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.951

Gnomad AMR AF: 0.860

Gnomad ASJ AF: 0.888

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.726

Gnomad FIN AF: 0.846

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.858

GnomAD3 exomes AF: 0.862 AC: 216072 AN: 250696 Hom.: 94363 AF XY: 0.863 AC XY: 116899 AN XY: 135530

Gnomad AFR exome AF: 0.622

Gnomad AMR exome AF: 0.850

Gnomad ASJ exome AF: 0.884

Gnomad EAS exome AF: 0.860

Gnomad SAS exome AF: 0.730

Gnomad FIN exome AF: 0.847

Gnomad NFE exome AF: 0.935

Gnomad OTH exome AF: 0.891

GnomAD4 exome AF: 0.913 AC: 1262843 AN: 1383706 Hom.: 580228 Cov.: 20 AF XY: 0.909 AC XY: 629440 AN XY: 692668

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.848

Gnomad4 ASJ exome AF: 0.882

Gnomad4 EAS exome AF: 0.878

Gnomad4 SAS exome AF: 0.737

Gnomad4 FIN exome AF: 0.852

Gnomad4 NFE exome AF: 0.945

Gnomad4 OTH exome AF: 0.891

GnomAD4 genome AF: 0.831 AC: 126375 AN: 151994 Hom.: 53770 Cov.: 30 AF XY: 0.826 AC XY: 61358 AN XY: 74276

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.860

Gnomad4 ASJ AF: 0.888

Gnomad4 EAS AF: 0.875

Gnomad4 SAS AF: 0.727

Gnomad4 FIN AF: 0.846

Gnomad4 NFE AF: 0.941

Gnomad4 OTH AF: 0.854

Alfa AF: 0.918 Hom.: 125382

Bravo AF: 0.825

Asia WGS AF: 0.760 AC: 2639 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Nov 12, 2023	This variant is classified as Benign based on local population frequency. This variant was detected in 99% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -
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	-0.77
CADD	Benign	1.0
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs186080; hg19: chr4-151765243;