dbSNP rs150102345: LRBA:c.*9G>T (chr4-150265713-C-A) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_001364905.1(LRBA):c.*9G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0028 in 1,579,606 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0029 ( 15 hom. )

Consequence

LRBA
NM_001364905.1 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.0920

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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 4-150265713-C-A is Benign according to our data. Variant chr4-150265713-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282955.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00221 (337/152316) while in subpopulation AMR AF = 0.00497 (76/15306). AF 95% confidence interval is 0.00407. There are 2 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

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.*9G>T	3_prime_UTR	Exon 57 of 57	NP_001351834.1	A0A494C1L5
LRBA	NM_001440430.1		c.*9G>T	3_prime_UTR	Exon 58 of 58	NP_001427359.1
LRBA	NM_006726.5		c.*9G>T	3_prime_UTR	Exon 58 of 58	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRBA	ENST00000651943.2	MANE Select	c.*9G>T	3_prime_UTR	Exon 57 of 57	ENSP00000498582.2	A0A494C1L5
LRBA	ENST00000357115.9	TSL:1	c.*9G>T	3_prime_UTR	Exon 58 of 58	ENSP00000349629.3	P50851-1
LRBA	ENST00000510413.5	TSL:1	c.*9G>T	3_prime_UTR	Exon 57 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

337

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000820

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00325

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00194

AC:

484

AN:

250072

AF XY:

0.00171

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00289

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00315

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00287

AC:

4093

AN:

1427290

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

1930

AN XY:

712358

show subpopulations

African (AFR)

AF:

0.000579

AC:

AN:

32798

American (AMR)

AF:

0.00295

AC:

132

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.000386

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39530

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85600

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00349

AC:

3769

AN:

1080386

Other (OTH)

AF:

0.00255

AC:

151

AN:

59254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

170

340

511

681

851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

276

414

552

690

<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:

0.00221

AC:

337

AN:

152316

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41566

American (AMR)

AF:

0.00497

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00325

AC:

221

AN:

68030

Other (OTH)

AF:

0.00237

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.00202

Hom.:

Bravo

AF:

0.00257

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

1.5

(source)

DANN

Benign

0.68

PhyloP100

0.092

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over