NM_001364905.1:c.3874G>A

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.3874G>A(p.Val1292Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,900 control chromosomes in the GnomAD database, including 26 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 (★★).

Frequency

Genomes: 𝑓 0.0076 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00076 ( 14 hom. )

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.340

Publications

2 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=0.0033608973).

BP6

Variant 4-150850854-C-T is Benign according to our data. Variant chr4-150850854-C-T is described in ClinVar as [Benign]. Clinvar id is 473175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00756 (1152/152318) while in subpopulation AFR AF = 0.0264 (1098/41562). AF 95% confidence interval is 0.0251. There are 12 homozygotes in GnomAd4. There are 539 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1 link	c.3874G>A	p.Val1292Ile	missense_variant	Exon 24 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.3874G>A	p.Val1292Ile	missense_variant	Exon 24 of 57		NM_001364905.1	ENSP00000498582.2		A0A494C1L5

Frequencies

GnomAD3 genomes

AF:

0.00754

AC:

1147

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00187

AC:

469

AN:

251068

AF XY:

0.00130

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.000521

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000763

AC:

1115

AN:

1461582

Hom.:

Cov.:

AF XY:

0.000626

AC XY:

455

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0277

AC:

927

AN:

33458

American (AMR)

AF:

0.000962

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000342

AC:

AN:

1111866

Other (OTH)

AF:

0.00162

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

149

198

248

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00756

AC:

1152

AN:

152318

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

539

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.0264

AC:

1098

AN:

41562

American (AMR)

AF:

0.00261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68030

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00857

ESP6500AA

AF:

0.0286

AC:

126

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

- -

not specified

Benign:1

Jan 04, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.018

.;T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.59

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;.

PhyloP100

0.34

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.48

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.066

B;B;.

Vest4

0.067

MVP

0.38

MPC

0.092

ClinPred

0.0053

GERP RS

4.1

Varity_R

0.029

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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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NM_001364905.1:c.3874G>A

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