Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001364905.1(LRBA):c.6781-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,612,926 control chromosomes in the GnomAD database, including 304 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 152 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 152 hom. )

Consequence

LRBA
NM_001364905.1 splice_region, intron

Scores

Splicing: ADA: 0.3400

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.32

Publications

4 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 4-150436867-G-A is Benign according to our data. Variant chr4-150436867-G-A is described in ClinVar as Benign. ClinVar VariationId is 473183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0792 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	Effect	Exon Rank	Protein
LRBA	NM_001364905.1	MANE Select	c.6781-3C>T	splice_region intron	N/A	NP_001351834.1
LRBA	NM_001440430.1		c.6814-3C>T	splice_region intron	N/A	NP_001427359.1
LRBA	NM_006726.5		c.6814-3C>T	splice_region intron	N/A	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LRBA	ENST00000651943.2	MANE Select	c.6781-3C>T	splice_region intron	N/A	ENSP00000498582.2
LRBA	ENST00000357115.9	TSL:1	c.6814-3C>T	splice_region intron	N/A	ENSP00000349629.3
LRBA	ENST00000510413.5	TSL:1	c.6781-3C>T	splice_region intron	N/A	ENSP00000421552.1

Frequencies

GnomAD3 genomes

AF:

0.0240

AC:

3646

AN:

152030

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0815

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00686

AC:

1716

AN:

250128

AF XY:

0.00554

show subpopulations

Gnomad AFR exome

AF:

0.0828

Gnomad AMR exome

AF:

0.00397

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.00410

GnomAD4 exome

AF:

0.00293

AC:

4281

AN:

1460778

Hom.:

152

Cov.:

AF XY:

0.00278

AC XY:

2019

AN XY:

726736

show subpopulations

African (AFR)

AF:

0.0850

AC:

2839

AN:

33396

American (AMR)

AF:

0.00473

AC:

211

AN:

44578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00151

AC:

AN:

39652

South Asian (SAS)

AF:

0.00418

AC:

360

AN:

86098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00728

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000352

AC:

391

AN:

1111444

Other (OTH)

AF:

0.00626

AC:

378

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

175

350

526

701

876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.0240

AC:

3653

AN:

152148

Hom.:

152

Cov.:

AF XY:

0.0233

AC XY:

1731

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0815

AC:

3382

AN:

41504

American (AMR)

AF:

0.0107

AC:

163

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00213

AC:

AN:

5170

South Asian (SAS)

AF:

0.00374

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

67994

Other (OTH)

AF:

0.0156

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

159

318

477

636

795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0131

Hom.:

Bravo

AF:

0.0272

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to LRBA deficiency (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

1.3

PromoterAI

-0.058

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.34

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.14

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over