4-150852441-G-C

Variant names:

• chr4-150852441-G-C
• rs1782360
• NM_001364905.1:c.3269C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364905.1(LRBA):​c.3269C>G​(p.Ala1090Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.084 in 1,612,950 control chromosomes in the GnomAD database, including 9,262 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1601 hom., cov: 32)
  • Exomes 𝑓: 0.080 (7661 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0310
• Publications: 27 publications found

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]

LRBA Gene-Disease associations (from GenCC):

• combined immunodeficiency due to LRBA deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ENSG00000298996 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027665794).
• BP6: Variant 4-150852441-G-C is Benign according to our data. Variant chr4-150852441-G-C is described in ClinVar as Benign. ClinVar VariationId is 281585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.3269C>G	p.Ala1090Gly	missense_variant	Exon 23 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.3269C>G	p.Ala1090Gly	missense_variant	Exon 23 of 57		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19079 AN: 151926 Hom.: 1596 Cov.: 32

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.118

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.106

GnomAD2 exomes AF: 0.124 AC: 31064 AN: 250652 AF XY: 0.126

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0798

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.0613

Gnomad OTH exome AF: 0.0997

GnomAD4 exome AF: 0.0797 AC: 116423 AN: 1460906 Hom.: 7661 Cov.: 33 AF XY: 0.0843 AC XY: 61252 AN XY: 726814

African (AFR) AF: 0.243 AC: 8135 AN: 33462

American (AMR) AF: 0.140 AC: 6276 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0823 AC: 2150 AN: 26132

East Asian (EAS) AF: 0.123 AC: 4862 AN: 39678

South Asian (SAS) AF: 0.260 AC: 22442 AN: 86234

European-Finnish (FIN) AF: 0.148 AC: 7812 AN: 52738

Middle Eastern (MID) AF: 0.0971 AC: 560 AN: 5768

European-Non Finnish (NFE) AF: 0.0526 AC: 58494 AN: 1111802

Other (OTH) AF: 0.0943 AC: 5692 AN: 60370

GnomAD4 genome AF: 0.126 AC: 19110 AN: 152044 Hom.: 1601 Cov.: 32 AF XY: 0.133 AC XY: 9897 AN XY: 74300

African (AFR) AF: 0.226 AC: 9380 AN: 41464

American (AMR) AF: 0.118 AC: 1800 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3468

East Asian (EAS) AF: 0.125 AC: 647 AN: 5182

South Asian (SAS) AF: 0.272 AC: 1306 AN: 4810

European-Finnish (FIN) AF: 0.154 AC: 1621 AN: 10548

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0556 AC: 3781 AN: 67992

Other (OTH) AF: 0.110 AC: 231 AN: 2108

Alfa AF: 0.0682 Hom.: 357

Bravo AF: 0.126

TwinsUK AF: 0.0491 AC: 182

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.223 AC: 982

ESP6500EA AF: 0.0586 AC: 504

ExAC AF: 0.127 AC: 15447

Asia WGS AF: 0.228 AC: 792 AN: 3478

EpiCase AF: 0.0557

EpiControl AF: 0.0591

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 15, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 24% of patients studied by a panel of primary immunodeficiencies. Number of patients: 23. Only high quality variants are reported.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 15, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Combined immunodeficiency due to LRBA deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Benign	0.90
DEOGEN2	Benign	0.0	.;T;.
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0028	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;.
PhyloP100		0.031
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.091	T;T;T
Sift4G	Benign	0.36	T;T;T
Vest4		0.078
ClinPred		0.0015	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1782360; hg19: chr4-151773593; COSMIC: COSV63956045; COSMIC: COSV63956045;