rs116355217

chr4-150908428-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001364905.1(LRBA):c.1399A>G(p.Met467Val) variant causes a missense change. The variant allele was found at a frequency of 0.00329 in 1,608,406 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (8 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:3
• Conservation: PhyloP100: 4.28

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015882492).
• BP6: Variant 4-150908428-T-C is Benign according to our data. Variant chr4-150908428-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287150.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=7}. Variant chr4-150908428-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (321/152306) while in subpopulation NFE AF= 0.00363 (247/68014). AF 95% confidence interval is 0.00326. There are 1 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.1399A>G	p.Met467Val	missense_variant	11/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.1399A>G	p.Met467Val	missense_variant	11/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00212 AC: 521 AN: 245372 Hom.: 1 AF XY: 0.00219 AC XY: 290 AN XY: 132456

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00341 AC: 4963 AN: 1456100 Hom.: 8 Cov.: 30 AF XY: 0.00329 AC XY: 2385 AN XY: 723922

Gnomad4 AFR exome AF: 0.000392

Gnomad4 AMR exome AF: 0.000512

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000119

Gnomad4 FIN exome AF: 0.00141

Gnomad4 NFE exome AF: 0.00422

Gnomad4 OTH exome AF: 0.00266

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74478

Gnomad4 AFR AF: 0.000721

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00363

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00334 Hom.: 2

Bravo AF: 0.00203

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00215 AC: 261

EpiCase AF: 0.00344

EpiControl AF: 0.00326

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Uncertain:4 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 15, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 15, 2021	The LRBA c.1399A>G; p.Met467Val variant (rs116355217) is reported in the literature in an individual with common variable immunodeficiency that carried a second missense variant in LRBA (Maffucci 2016). The p.Met467Val variant is reported in ClinVar (Variation ID: 287150) and is found in the general population with an overall allele frequency of 0.22% (606/276772 alleles, including a single homozygote) in the Genome Aggregation Database. The methionine at codon 467 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.163). Due to limited information, the clinical significance of the p.Met467Val variant is uncertain at this time. References: Maffucci et al. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol. 2016 Jun 13;7:220. -
Uncertain significance, criteria provided, single submitter	clinical testing	Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	May 17, 2022	The c.1399A>G variant is present in publicly available population databases like 1000 Genomes, EVS, ExAC and gnomAD, at a low frequency. The variant is not present in Indian Exome Database and our in-house exome database. The variant was previously reported to ClinVar (Accession: VCV000287150.24) with conflicitng interpretations of pathogencicity (Uncertain significance/likely benign/benign) in association with combined immunodeficiency due to LRBA deficiency. The variant was previously identified in similarly affected individuals (PMID: 27379089, 28956255) and reported to Human Genome Mutation Database (HGMD ID: CM167684). Predictions from different in-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. are contradictory, however these predictions were not confirmed by any published functional studies. -

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	LRBA: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 31, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 01, 2020	DNA sequence analysis of the LRBA gene demonstrated a sequence change, c.1399A>G, in exon 11 that results in an amino acid change, p.Met467Val. This sequence change has been described in the gnomAD database with a frequency of 0.4% in the European sub-population (dbSNP rs116355217). The p.Met467Va sequence change has been reported in one patient with common variable immunodeficiency who also had a second missense variant present in the LRBA gene, however functional and/or segregation studies were not performed to clarify the clinical significance of this sequence change (PMID: 27379089). The p.Met467Val change affects a moderately conserved amino acid residue located in a domain of the LRBA protein that is known to be functional. The p.Met467Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Met467Val change remains unknown at this time. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.016	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		0.0070	B;B;B
Vest4		0.78
MVP		0.41
MPC		0.12
ClinPred		0.029	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs116355217; hg19: chr4-151829580;