rs139428189

Positions:

• chr4-150868229-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001364905.1(LRBA):​c.2526T>C​(p.Phe842=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,612,782 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.47

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-150868229-A-G is Benign according to our data. Variant chr4-150868229-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 289297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00362 (551/152332) while in subpopulation NFE AF= 0.0056 (381/68028). AF 95% confidence interval is 0.00514. There are 3 homozygotes in gnomad4. There are 256 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.2526T>C	p.Phe842=	synonymous_variant	21/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.2526T>C	p.Phe842=	synonymous_variant	21/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152214 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00226

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00560

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00314 AC: 787 AN: 250880 Hom.: 5 AF XY: 0.00313 AC XY: 425 AN XY: 135608

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00666

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00455

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00346 AC: 5056 AN: 1460450 Hom.: 11 Cov.: 30 AF XY: 0.00351 AC XY: 2549 AN XY: 726584

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.00697

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00298

Gnomad4 NFE exome AF: 0.00384

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00362 AC: 551 AN: 152332 Hom.: 3 Cov.: 32 AF XY: 0.00344 AC XY: 256 AN XY: 74498

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00226

Gnomad4 NFE AF: 0.00560

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00463 Hom.: 2

Bravo AF: 0.00302

EpiCase AF: 0.00576

EpiControl AF: 0.00504

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 14, 2021	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

LRBA: BP4, BP7, BS2 -

LRBA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.7
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs139428189; hg19: chr4-151789381;