dbSNP rs1163872504: LRBA:c.217-9C>T (chr4-150929074-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_001364905.1(LRBA):c.217-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000429 in 1,101,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LRBA
NM_001364905.1 intron

Scores

Splicing: ADA: 0.00001682

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0950

Publications

0 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

LRBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 4-150929074-G-A is Benign according to our data. Variant chr4-150929074-G-A is described in ClinVar as Benign. ClinVar VariationId is 473171.Status of the report is criteria_provided_single_submitter, 1 stars.

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	UniProt
LRBA	NM_001364905.1	MANE Select	c.217-9C>T	intron	N/A	NP_001351834.1	A0A494C1L5
LRBA	NM_001440430.1		c.217-9C>T	intron	N/A	NP_001427359.1
LRBA	NM_006726.5		c.217-9C>T	intron	N/A	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRBA	ENST00000651943.2	MANE Select	c.217-9C>T	intron	N/A	ENSP00000498582.2	A0A494C1L5
LRBA	ENST00000357115.9	TSL:1	c.217-9C>T	intron	N/A	ENSP00000349629.3	P50851-1
LRBA	ENST00000510413.5	TSL:1	c.217-9C>T	intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes

AF:

0.000307

AC:

AN:

133356

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000108

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000227

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00353

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000115

Gnomad OTH

AF:

0.000541

GnomAD2 exomes

AF:

0.00183

AC:

149

AN:

81360

AF XY:

0.00171

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00212

Gnomad EAS exome

AF:

0.00107

Gnomad FIN exome

AF:

0.000990

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.00317

GnomAD4 exome

AF:

0.000429

AC:

472

AN:

1101270

Hom.:

Cov.:

AF XY:

0.000435

AC XY:

239

AN XY:

548844

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00168

AC:

AN:

25574

American (AMR)

AF:

0.00214

AC:

AN:

29970

Ashkenazi Jewish (ASJ)

AF:

0.000708

AC:

AN:

19762

East Asian (EAS)

AF:

0.000200

AC:

AN:

30038

South Asian (SAS)

AF:

0.000734

AC:

AN:

62688

European-Finnish (FIN)

AF:

0.000396

AC:

AN:

37904

Middle Eastern (MID)

AF:

0.000875

AC:

AN:

4570

European-Non Finnish (NFE)

AF:

0.000310

AC:

262

AN:

845228

Other (OTH)

AF:

0.000395

AC:

AN:

45536

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.283

Heterozygous variant carriers

122

163

204

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000307

AC:

AN:

133356

Hom.:

Cov.:

AF XY:

0.000343

AC XY:

AN XY:

64098

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000108

AC:

AN:

37058

American (AMR)

AF:

0.000227

AC:

AN:

13214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3198

East Asian (EAS)

AF:

0.00

AC:

AN:

4584

South Asian (SAS)

AF:

0.00

AC:

AN:

4104

European-Finnish (FIN)

AF:

0.00353

AC:

AN:

7356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000115

AC:

AN:

60912

Other (OTH)

AF:

0.000541

AC:

AN:

1848

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.268

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00334

Hom.:

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined immunodeficiency due to LRBA deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.15

PhyloP100

0.095

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000017

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

Other links and lift over