rs2290846

Variant names:

• chr4-150277928-G-A
• rs2290846
• NM_001364905.1:c.8393C>T

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.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. 14/21 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:5
• Conservation: PhyloP100: 3.06
• Publications: 47 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.8393C>T	p.Ser2798Leu	missense_variant	Exon 56 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.8393C>T	p.Ser2798Leu	missense_variant	Exon 56 of 57		NM_001364905.1	ENSP00000498582.2

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

GnomAD2 exomes AF: 0.201 AC: 50509 AN: 251200 AF XY: 0.203

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 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

African (AFR) AF: 0.0414 AC: 1386 AN: 33480

American (AMR) AF: 0.115 AC: 5150 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 3744 AN: 26136

East Asian (EAS) AF: 0.282 AC: 11182 AN: 39696

South Asian (SAS) AF: 0.112 AC: 9631 AN: 86248

European-Finnish (FIN) AF: 0.216 AC: 11514 AN: 53364

Middle Eastern (MID) AF: 0.174 AC: 1005 AN: 5768

European-Non Finnish (NFE) AF: 0.282 AC: 313312 AN: 1111916

Other (OTH) AF: 0.231 AC: 13968 AN: 60388

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

African (AFR) AF: 0.0471 AC: 1955 AN: 41506

American (AMR) AF: 0.154 AC: 2354 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 517 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1430 AN: 5134

South Asian (SAS) AF: 0.103 AC: 497 AN: 4826

European-Finnish (FIN) AF: 0.211 AC: 2233 AN: 10568

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18488 AN: 67972

Other (OTH) AF: 0.185 AC: 390 AN: 2108

Alfa AF: 0.236 Hom.: 16532

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 31% of patients studied by a panel of primary immunodeficiencies. Number of patients: 30. Only high quality variants are reported. -

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	0.12
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;T;.
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
MutationAssessor	Benign	1.2	.;L;.
PhyloP100		3.1
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
Mutation Taster		=100/0	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: rs2290846; hg19: chr4-151199080; COSMIC: COSV63949643;