rs140666848

chr4-150870530-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.2444A>G(p.Asn815Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,563,408 control chromosomes in the GnomAD database, including 8 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. N815N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (7 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 7.87

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=0.017331034).
• BP6: Variant 4-150870530-T-C is Benign according to our data. Variant chr4-150870530-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218542.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=2}. Variant chr4-150870530-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00213 (324/152264) while in subpopulation NFE AF= 0.00385 (262/68010). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.2444A>G	p.Asn815Ser	missense_variant	20/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.2444A>G	p.Asn815Ser	missense_variant	20/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00214 AC: 325 AN: 152150 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00254

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00387

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00221 AC: 553 AN: 250170 Hom.: 2 AF XY: 0.00222 AC XY: 300 AN XY: 135282

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000950

Gnomad FIN exome AF: 0.00256

Gnomad NFE exome AF: 0.00379

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00237 AC: 3344 AN: 1411144 Hom.: 7 Cov.: 25 AF XY: 0.00227 AC XY: 1601 AN XY: 705364

Gnomad4 AFR exome AF: 0.000215

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.000659

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.000892

Gnomad4 FIN exome AF: 0.00247

Gnomad4 NFE exome AF: 0.00277

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00213 AC: 324 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74444

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00254

Gnomad4 NFE AF: 0.00385

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00303 Hom.: 1

Bravo AF: 0.00178

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00252 AC: 306

Asia WGS AF: 0.000578 AC: 2 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	LRBA: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2021	Identified in two consanguinious LRBA-deficient siblings in the published literature with primary immunodeficiency who also had a homozygous frameshift variant in the LRBA gene that was believed to be the cause of their symptoms (Seidel et al., 2015); Identified in multiple affected relatives in a large pedigree in the published literature with Hirschsprung disease in addition to a relative with functional constipation and multiple unaffected relatives (Sribudiani et al., 2018); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25539626, 29601828) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Jul 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2015	- -

Hirschsprung disease, susceptibility to, 1 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Genetics, Erasmus University Medical Center

Nov 18, 2016

- -

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

LRBA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2022

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	Pathogenic	0.58
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.017	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.7	M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.4	D;D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.98	D;P;.
Vest4		0.80
MVP		0.63
MPC		0.50
ClinPred		0.038	T
GERP RS		4.5
Varity_R		0.43
gMVP		0.64

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: rs140666848; hg19: chr4-151791682; COSMIC: COSV105254217;