rs3749574

Variant names:

• chr4-150285975-C-T
• rs3749574
• NM_001364905.1:c.8077G>A

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.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. 15/21 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:6
• Conservation: PhyloP100: 1.95
• Publications: 32 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=0.006324917).
• BP6: Variant 4-150285975-C-T is Benign according to our data. Variant chr4-150285975-C-T is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.8077G>A	p.Ala2693Thr	missense_variant	Exon 54 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.8077G>A	p.Ala2693Thr	missense_variant	Exon 54 of 57		NM_001364905.1	ENSP00000498582.2

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

GnomAD2 exomes AF: 0.209 AC: 47361 AN: 226736 AF XY: 0.210

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 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

African (AFR) AF: 0.0642 AC: 2129 AN: 33166

American (AMR) AF: 0.128 AC: 5354 AN: 41788

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4402 AN: 25786

East Asian (EAS) AF: 0.276 AC: 10669 AN: 38722

South Asian (SAS) AF: 0.124 AC: 10289 AN: 83010

European-Finnish (FIN) AF: 0.226 AC: 11836 AN: 52480

Middle Eastern (MID) AF: 0.208 AC: 1199 AN: 5756

European-Non Finnish (NFE) AF: 0.310 AC: 341510 AN: 1102854

Other (OTH) AF: 0.260 AC: 15501 AN: 59700

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

African (AFR) AF: 0.0716 AC: 2972 AN: 41522

American (AMR) AF: 0.186 AC: 2838 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 620 AN: 3464

East Asian (EAS) AF: 0.280 AC: 1451 AN: 5180

South Asian (SAS) AF: 0.115 AC: 556 AN: 4820

European-Finnish (FIN) AF: 0.223 AC: 2360 AN: 10564

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.299 AC: 20336 AN: 67986

Other (OTH) AF: 0.217 AC: 458 AN: 2110

Alfa AF: 0.261 Hom.: 16820

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 35% of patients studied by a panel of primary immunodeficiencies. Number of patients: 34. Only high quality variants are reported. -

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 -

Combined immunodeficiency due to LRBA deficiency Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 09, 2021

GeneDx

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	0.069
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.022	.;T;.
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
MutationAssessor	Benign	0.95	.;L;.
PhyloP100		2.0
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
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3749574; hg19: chr4-151207127; COSMIC: COSV63966388;