rs72719663

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001364905.1(LRBA):c.2170A>G(p.Ile724Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,550,800 control chromosomes in the GnomAD database, including 615 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 42 hom., cov: 32)

Exomes 𝑓: 0.027 ( 573 hom. )

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.09

Publications

14 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=0.0076279044).

BP6

Variant 4-150872751-T-C is Benign according to our data. Variant chr4-150872751-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0191 (2910/152228) while in subpopulation NFE AF = 0.0281 (1910/68000). AF 95% confidence interval is 0.027. There are 42 homozygotes in GnomAd4. There are 1421 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1 link	c.2170A>G	p.Ile724Val	missense_variant	Exon 18 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.2170A>G	p.Ile724Val	missense_variant	Exon 18 of 57		NM_001364905.1	ENSP00000498582.2		A0A494C1L5

Frequencies

GnomAD3 genomes

AF:

0.0191

AC:

2910

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00420

Gnomad AMI

AF:

0.0899

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0265

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0281

Gnomad OTH

AF:

0.0196

GnomAD2 exomes

AF:

0.0212

AC:

5119

AN:

241228

AF XY:

0.0225

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.0111

Gnomad ASJ exome

AF:

0.0281

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0204

Gnomad NFE exome

AF:

0.0286

Gnomad OTH exome

AF:

0.0254

GnomAD4 exome

AF:

0.0267

AC:

37287

AN:

1398572

Hom.:

573

Cov.:

AF XY:

0.0270

AC XY:

18841

AN XY:

698352

show subpopulations

African (AFR)

AF:

0.00393

AC:

125

AN:

31826

American (AMR)

AF:

0.0115

AC:

479

AN:

41616

Ashkenazi Jewish (ASJ)

AF:

0.0277

AC:

705

AN:

25418

East Asian (EAS)

AF:

0.0000515

AC:

AN:

38798

South Asian (SAS)

AF:

0.0251

AC:

2039

AN:

81302

European-Finnish (FIN)

AF:

0.0220

AC:

1165

AN:

52878

Middle Eastern (MID)

AF:

0.0273

AC:

153

AN:

5608

European-Non Finnish (NFE)

AF:

0.0293

AC:

31193

AN:

1063156

Other (OTH)

AF:

0.0246

AC:

1426

AN:

57970

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1533

3066

4598

6131

7664

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1156

2312

3468

4624

5780

<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:

0.0191

AC:

2910

AN:

152228

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

1421

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00416

AC:

173

AN:

41566

American (AMR)

AF:

0.0165

AC:

252

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0265

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0275

AC:

133

AN:

4832

European-Finnish (FIN)

AF:

0.0207

AC:

219

AN:

10574

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0281

AC:

1910

AN:

68000

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

147

293

440

586

733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0257

Hom.:

170

Bravo

AF:

0.0176

TwinsUK

AF:

0.0318

AC:

118

ALSPAC

AF:

0.0298

AC:

115

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0306

AC:

263

ExAC

AF:

0.0216

AC:

2629

Asia WGS

AF:

0.00608

AC:

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency

Benign:3

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jan 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Benign:2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.031

.;T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0076

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.36

N;N;.

PhyloP100

1.1

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.58

N;N;N

REVEL

Benign

0.052

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.43

T;T;T

Polyphen

0.0010

B;B;.

Vest4

0.097

MPC

0.095

ClinPred

0.011

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.034

gMVP

0.068

Mutation Taster

=100/0

polymorphism (auto)

(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