rs2290846

Positions:

• chr4-150277928-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.8393C>T​(p.Ser2798Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,782 control chromosomes in the GnomAD database, including 53,568 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S2798S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (3399 hom., cov: 32)
  • Exomes 𝑓: 0.25 (50169 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.06

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=0.0014055073).
• BP6: Variant 4-150277928-G-A is Benign according to our data. Variant chr4-150277928-G-A is described in ClinVar as [Benign]. Clinvar id is 403047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.8393C>T	p.Ser2798Leu	missense_variant	56/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.8393C>T	p.Ser2798Leu	missense_variant	56/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28233 AN: 151948 Hom.: 3399 Cov.: 32

Gnomad AFR AF: 0.0472

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.154

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.201 AC: 50509 AN: 251200 Hom.: 6000 AF XY: 0.203 AC XY: 27510 AN XY: 135780

Gnomad AFR exome AF: 0.0449

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.109

Gnomad FIN exome AF: 0.216

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.254 AC: 370892 AN: 1461716 Hom.: 50169 Cov.: 34 AF XY: 0.249 AC XY: 181233 AN XY: 727162

Gnomad4 AFR exome AF: 0.0414

Gnomad4 AMR exome AF: 0.115

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.282

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.186 AC: 28229 AN: 152066 Hom.: 3399 Cov.: 32 AF XY: 0.180 AC XY: 13384 AN XY: 74328

Gnomad4 AFR AF: 0.0471

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.149

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.211

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.185

Alfa AF: 0.247 Hom.: 12140

Bravo AF: 0.178

TwinsUK AF: 0.295 AC: 1093

ALSPAC AF: 0.288 AC: 1109

ESP6500AA AF: 0.0531 AC: 234

ESP6500EA AF: 0.268 AC: 2302

ExAC AF: 0.203 AC: 24590

Asia WGS AF: 0.120 AC: 418 AN: 3478

EpiCase AF: 0.266

EpiControl AF: 0.261

ClinVar

Significance: Benign

Submissions summary: Benign:4

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. 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:1

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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.13	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.37	N;N;.
REVEL	Benign	0.044
Sift	Benign	0.33	T;T;.
Sift4G	Benign	0.27	T;T;.
Polyphen		0.049	B;B;.
Vest4		0.46
MPC		0.46
ClinPred		0.015	T
GERP RS		4.4
Varity_R		0.067
gMVP		0.15

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: rs2290846; hg19: chr4-151199080; COSMIC: COSV63949643;