rs17027133

chr4-150828321-T-C

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.5030A>G(p.Asn1677Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000873 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1677N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 5.76

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=0.009606034).
• BP6: Variant 4-150828321-T-C is Benign according to our data. Variant chr4-150828321-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540408.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=3, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00333 (508/152342) while in subpopulation AFR AF= 0.0107 (446/41582). AF 95% confidence interval is 0.0099. There are 2 homozygotes in gnomad4. There are 221 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.5030A>G	p.Asn1677Ser	missense_variant	30/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.5030A>G	p.Asn1677Ser	missense_variant	30/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152224 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00113 AC: 284 AN: 251350 Hom.: 0 AF XY: 0.000994 AC XY: 135 AN XY: 135836

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000616 AC: 901 AN: 1461826 Hom.: 1 Cov.: 32 AF XY: 0.000627 AC XY: 456 AN XY: 727214

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000515

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.00154

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000133

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00333 AC: 508 AN: 152342 Hom.: 2 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74504

Gnomad4 AFR AF: 0.0107

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000816 Hom.: 1

Bravo AF: 0.00338

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Oct 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	May 17, 2022	The c.5030A>G variant is present in publicly available population databases like 1000 Genomes, Exome Variant Server (EVS), Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and Indian Exome Database, at a low frequency. The variant is also present in our in-house exome database. The variant was previously reported to ClinVar (Accession: VCV000540408.9) with conflicitng interpretations of pathogenicity (Uncertain significane/benign) in association with combined immunodeficiency due to LRBA deficiency. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2017	Although the p.Asn1677Ser variant (rs17027133) has not been reported in the medical literature, it is listed in the Genome Aggregation Database (gnomAD) browser with an allele frequency of 0.99% in the African population (identified in 238 out of 24,032 chromosomes). The asparagine at codon 1677 is moderately conserved considering 13 species (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the LRBA protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). However, based on the available information, the clinical significance of the p.Asn1677Ser variant cannot be determined with certainty. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	LRBA: BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 04, 2021	- -

LRBA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 09, 2020

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	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D;D;D
MetaRNN	Benign	0.0096	T;T;T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Pathogenic	3.2	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D;D;D
Sift4G	Benign	0.12	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.36
MVP		0.73
MPC		0.49
ClinPred		0.050	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17027133; hg19: chr4-151749473;