rs143754610

chr4-150905994-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001364905.1(LRBA):c.1603-4G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,608,056 control chromosomes in the GnomAD database, including 694 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 0.017 (136 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (558 hom.)
• Consequence: LRBA NM_001364905.1 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001193
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.430

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-150905994-C-A is Benign according to our data. Variant chr4-150905994-C-A is described in ClinVar as [Benign]. Clinvar id is 473168.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-150905994-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.1603-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.1603-4G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2626 AN: 151734 Hom.: 135 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0560

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00311

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0281 AC: 6925 AN: 246602 Hom.: 307 AF XY: 0.0244 AC XY: 3249 AN XY: 133382

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.0890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0533

Gnomad SAS exome AF: 0.000772

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.00925 AC: 13473 AN: 1456204 Hom.: 558 Cov.: 30 AF XY: 0.00873 AC XY: 6322 AN XY: 724400

Gnomad4 AFR exome AF: 0.00121

Gnomad4 AMR exome AF: 0.0883

Gnomad4 ASJ exome AF: 0.0000386

Gnomad4 EAS exome AF: 0.0496

Gnomad4 SAS exome AF: 0.000985

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00970

GnomAD4 genome AF: 0.0173 AC: 2627 AN: 151852 Hom.: 136 Cov.: 31 AF XY: 0.0232 AC XY: 1723 AN XY: 74186

Gnomad4 AFR AF: 0.00162

Gnomad4 AMR AF: 0.0561

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0477

Gnomad4 SAS AF: 0.00354

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.00311

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00490 Hom.: 4

Bravo AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	3.7
Dann	Benign	0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143754610; hg19: chr4-151827146; COSMIC: COSV63956050;