rs140666848

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001364905.1(LRBA):c.2444A>G(p.Asn815Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,563,408 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N815N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0024 ( 7 hom. )

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:8

Conservation

PhyloP100: 7.87

Publications

9 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017331034).

BP6

Variant 4-150870530-T-C is Benign according to our data. Variant chr4-150870530-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218542.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00213 (324/152264) while in subpopulation NFE AF = 0.00385 (262/68010). AF 95% confidence interval is 0.00347. There are 1 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1 link	c.2444A>G	p.Asn815Ser	missense_variant	Exon 20 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2 link	c.2444A>G	p.Asn815Ser	missense_variant	Exon 20 of 57		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes

AF:

0.00214

AC:

325

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00387

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.00221

AC:

553

AN:

250170

AF XY:

0.00222

show subpopulations

Gnomad AFR exome

AF:

0.000493

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00256

Gnomad NFE exome

AF:

0.00379

Gnomad OTH exome

AF:

0.00180

GnomAD4 exome

AF:

0.00237

AC:

3344

AN:

1411144

Hom.:

Cov.:

AF XY:

0.00227

AC XY:

1601

AN XY:

705364

show subpopulations

African (AFR)

AF:

0.000215

AC:

AN:

32494

American (AMR)

AF:

0.000381

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.000659

AC:

AN:

25780

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39292

South Asian (SAS)

AF:

0.000892

AC:

AN:

85202

European-Finnish (FIN)

AF:

0.00247

AC:

130

AN:

52568

Middle Eastern (MID)

AF:

0.00476

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00277

AC:

2955

AN:

1066842

Other (OTH)

AF:

0.00194

AC:

114

AN:

58686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<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:

0.00213

AC:

324

AN:

152264

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41556

American (AMR)

AF:

0.000720

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000415

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00254

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00385

AC:

262

AN:

68010

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00268

Hom.:

Bravo

AF:

0.00178

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00252

AC:

306

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Apr 21, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Identified in two consanguinious LRBA-deficient siblings in the published literature with primary immunodeficiency who also had a homozygous frameshift variant in the LRBA gene that was believed to be the cause of their symptoms (Seidel et al., 2015); Identified in multiple affected relatives in a large pedigree in the published literature with Hirschsprung disease in addition to a relative with functional constipation and multiple unaffected relatives (Sribudiani et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25539626, 29601828) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

LRBA: BS2 -

not specified

Benign:3

Dec 02, 2015

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 20, 2019

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Nov 18, 2016

Clinical Genetics, Erasmus University Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Combined immunodeficiency due to LRBA deficiency

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

LRBA-related disorder

Benign:1

May 19, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.043

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Uncertain

2.7

M;M;.

PhyloP100

7.9

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-4.4

D;D;D

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

0.98

D;P;.

Vest4

0.80

MVP

0.63

MPC

0.50

ClinPred

0.038

GERP RS

4.5

Varity_R

0.43

gMVP

0.64

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over