4-150310219-T-C

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.7849+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 1,594,122 control chromosomes in the GnomAD database, including 340,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.62 (29855 hom., cov: 32)
  • Exomes 𝑓: 0.65 (310566 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.645

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=-0.72).
• BP6: Variant 4-150310219-T-C is Benign according to our data. Variant chr4-150310219-T-C is described in ClinVar as [Benign]. Clinvar id is 403049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150310219-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.7849+10A>G		intron_variant		ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.7849+10A>G		intron_variant			NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.623 AC: 94532 AN: 151844 Hom.: 29850 Cov.: 32

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.536

Gnomad ASJ AF: 0.668

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.685

Gnomad OTH AF: 0.624

GnomAD3 exomes AF: 0.596 AC: 148419 AN: 248818 Hom.: 46167 AF XY: 0.601 AC XY: 80885 AN XY: 134630

Gnomad AFR exome AF: 0.579

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.681

Gnomad EAS exome AF: 0.432

Gnomad SAS exome AF: 0.478

Gnomad FIN exome AF: 0.674

Gnomad NFE exome AF: 0.687

Gnomad OTH exome AF: 0.613

GnomAD4 exome AF: 0.651 AC: 938915 AN: 1442160 Hom.: 310566 Cov.: 26 AF XY: 0.648 AC XY: 465333 AN XY: 718182

Gnomad4 AFR exome AF: 0.580

Gnomad4 AMR exome AF: 0.435

Gnomad4 ASJ exome AF: 0.680

Gnomad4 EAS exome AF: 0.457

Gnomad4 SAS exome AF: 0.484

Gnomad4 FIN exome AF: 0.681

Gnomad4 NFE exome AF: 0.681

Gnomad4 OTH exome AF: 0.628

GnomAD4 genome AF: 0.622 AC: 94572 AN: 151962 Hom.: 29855 Cov.: 32 AF XY: 0.617 AC XY: 45811 AN XY: 74256

Gnomad4 AFR AF: 0.575

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.668

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.472

Gnomad4 FIN AF: 0.675

Gnomad4 NFE AF: 0.685

Gnomad4 OTH AF: 0.623

Alfa AF: 0.663 Hom.: 54050

Bravo AF: 0.607

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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 68% of patients studied by a panel of primary immunodeficiencies. Number of patients: 65. Only high quality variants are reported. -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

not provided Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	10
Dann	Benign	0.82

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: rs1813134; hg19: chr4-151231371; COSMIC: COSV63956175; COSMIC: COSV63956175;