rs3749574

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.95

Publications

32 publications found

Variant links:

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

LRBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364905.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRBA	NM_001364905.1	MANE Select	c.8077G>A	p.Ala2693Thr	missense	Exon 54 of 57	NP_001351834.1
LRBA	NM_001440430.1		c.8125G>A	p.Ala2709Thr	missense	Exon 55 of 58	NP_001427359.1
LRBA	NM_006726.5		c.8110G>A	p.Ala2704Thr	missense	Exon 55 of 58	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
LRBA	ENST00000651943.2	MANE Select	c.8077G>A	p.Ala2693Thr	missense	Exon 54 of 57	ENSP00000498582.2
LRBA	ENST00000357115.9	TSL:1	c.8110G>A	p.Ala2704Thr	missense	Exon 55 of 58	ENSP00000349629.3
LRBA	ENST00000510413.5	TSL:1	c.8074G>A	p.Ala2692Thr	missense	Exon 54 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes

AF:

0.210

AC:

31997

AN:

152008

Hom.:

4127

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.274

AC XY:

196493

AN XY:

716378

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

13444

26888

40333

53777

67221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11102

22204

33306

44408

55510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.210

AC:

31992

AN:

152126

Hom.:

4127

Cov.:

AF XY:

0.204

AC XY:

15143

AN XY:

74370

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.299

AC:

20336

AN:

67986

Other (OTH)

AF:

0.217

AC:

458

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1237

2474

3711

4948

6185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

344

688

1032

1376

1720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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

Combined immunodeficiency due to LRBA deficiency

Benign:2

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.022

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

2.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.40

REVEL

Benign

0.087

Sift

Benign

0.24

Sift4G

Benign

0.78

Polyphen

0.0010

Vest4

0.083

MPC

0.11

ClinPred

0.0047

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over