4-150798111-A-G

Position:

• chr4-150798111-A-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001364905.1(LRBA):​c.5550T>C​(p.Val1850=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,603,866 control chromosomes in the GnomAD database, including 41,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2905 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39067 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.44

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-150798111-A-G is Benign according to our data. Variant chr4-150798111-A-G is described in ClinVar as [Benign]. Clinvar id is 403050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.5550T>C	p.Val1850=	synonymous_variant	34/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.5550T>C	p.Val1850=	synonymous_variant	34/57		NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26094 AN: 151932 Hom.: 2906 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.163

GnomAD3 exomes AF: 0.183 AC: 46013 AN: 250976 Hom.: 4913 AF XY: 0.186 AC XY: 25261 AN XY: 135666

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.174

Gnomad SAS exome AF: 0.108

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.223 AC: 324041 AN: 1451816 Hom.: 39067 Cov.: 28 AF XY: 0.220 AC XY: 159189 AN XY: 722694

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.121

Gnomad4 EAS exome AF: 0.187

Gnomad4 SAS exome AF: 0.110

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.172 AC: 26086 AN: 152050 Hom.: 2905 Cov.: 32 AF XY: 0.171 AC XY: 12680 AN XY: 74332

Gnomad4 AFR AF: 0.0430

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.126

Gnomad4 EAS AF: 0.190

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.284

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.161

Alfa AF: 0.215 Hom.: 7101

Bravo AF: 0.158

Asia WGS AF: 0.105 AC: 364 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 30% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. 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 -

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	-	- -

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.4
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1129998; hg19: chr4-151719263; COSMIC: COSV63953265;