rs145709687

Positions:

• chr4-150265730-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001364905.1(LRBA):​c.8551C>T​(p.Arg2851Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,608,596 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2851H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 2.44

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05010733).
• BP6: Variant 4-150265730-G-A is Benign according to our data. Variant chr4-150265730-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287379.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00147 (224/152102) while in subpopulation NFE AF= 0.00269 (183/68016). AF 95% confidence interval is 0.00237. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.8551C>T	p.Arg2851Cys	missense_variant	57/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.8551C>T	p.Arg2851Cys	missense_variant	57/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 224 AN: 152102 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00125 AC: 311 AN: 249728 Hom.: 2 AF XY: 0.00126 AC XY: 170 AN XY: 135156

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000693

Gnomad NFE exome AF: 0.00226

Gnomad OTH exome AF: 0.000816

GnomAD4 exome AF: 0.00183 AC: 2660 AN: 1456494 Hom.: 3 Cov.: 28 AF XY: 0.00178 AC XY: 1293 AN XY: 724994

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000649

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.00147 AC: 224 AN: 152102 Hom.: 1 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74292

Gnomad4 AFR AF: 0.000411

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000472

Gnomad4 NFE AF: 0.00269

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Feb 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 20, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	LRBA: BS2 -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 13, 2016	- -

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

LRBA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2023

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
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.050	T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.2	D;D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.74
MVP		0.73
MPC		0.65
ClinPred		0.10	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.66
gMVP		0.53

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

LitVar

Other links and lift over

dbSNP: rs145709687; hg19: chr4-151186882;