rs3749574

Positions:

• chr4-150285975-C-T

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.8077G>A​(p.Ala2693Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,595,388 control chromosomes in the GnomAD database, including 64,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2693V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.21 (4127 hom., cov: 32)
  • Exomes 𝑓: 0.28 (59881 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.95

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 (MetaRNN=0.006324917).
• BP6: Variant 4-150285975-C-T is Benign according to our data. Variant chr4-150285975-C-T is described in ClinVar as [Benign]. Clinvar id is 403048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.8077G>A	p.Ala2693Thr	missense_variant	54/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.8077G>A	p.Ala2693Thr	missense_variant	54/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.210 AC: 31997 AN: 152008 Hom.: 4127 Cov.: 32

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.367

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.179

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.116

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.299

Gnomad OTH AF: 0.219

GnomAD3 exomes AF: 0.209 AC: 47361 AN: 226736 Hom.: 5601 AF XY: 0.210 AC XY: 25570 AN XY: 121826

Gnomad AFR exome AF: 0.0631

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.245

Gnomad SAS exome AF: 0.115

Gnomad FIN exome AF: 0.220

Gnomad NFE exome AF: 0.278

Gnomad OTH exome AF: 0.229

GnomAD4 exome AF: 0.279 AC: 402889 AN: 1443262 Hom.: 59881 Cov.: 32 AF XY: 0.274 AC XY: 196493 AN XY: 716378

Gnomad4 AFR exome AF: 0.0642

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.276

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.226

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.260

GnomAD4 genome AF: 0.210 AC: 31992 AN: 152126 Hom.: 4127 Cov.: 32 AF XY: 0.204 AC XY: 15143 AN XY: 74370

Gnomad4 AFR AF: 0.0716

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.179

Gnomad4 EAS AF: 0.280

Gnomad4 SAS AF: 0.115

Gnomad4 FIN AF: 0.223

Gnomad4 NFE AF: 0.299

Gnomad4 OTH AF: 0.217

Alfa AF: 0.273 Hom.: 12797

Bravo AF: 0.205

TwinsUK AF: 0.317 AC: 1176

ALSPAC AF: 0.313 AC: 1205

ESP6500AA AF: 0.0792 AC: 349

ESP6500EA AF: 0.297 AC: 2554

ExAC AF: 0.205 AC: 24854

Asia WGS AF: 0.135 AC: 472 AN: 3478

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. 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 -

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.044
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0063	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.40	N;N;.
REVEL	Benign	0.087
Sift	Benign	0.24	T;T;.
Sift4G	Benign	0.78	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.083
MPC		0.11
ClinPred		0.0047	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3749574; hg19: chr4-151207127; COSMIC: COSV63966388;