rs116355217

Variant names:

• chr4-150908428-T-C
• rs116355217
• NM_001364905.1:c.1399A>G

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.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:4
• 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 -13 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=3, 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.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.1399A>G	p.Met467Val	missense_variant	Exon 11 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.1399A>G	p.Met467Val	missense_variant	Exon 11 of 57		NM_001364905.1	ENSP00000498582.2

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:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Jan 15, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Jan 15, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 17, 2022

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:2 Benign:1

Aug 31, 2017

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

LRBA: BP4, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1 Benign:2

Apr 11, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LRBA c.1399A>G (p.Met467Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 245372 control chromosomes, predominantly at a frequency of 0.004 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in LRBA causing Common Variable Immunodeficiency 8, With Autoimmunity phenotype. c.1399A>G has been reported in the literature in individuals affected with Immunodeficiency (e.g. Maffucci_2016). These reports do not provide unequivocal conclusions about association of the variant with Common Variable Immunodeficiency 8, With Autoimmunity. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 27379089). ClinVar contains an entry for this variant (Variation ID: 287150). Based on the evidence outlined above, the variant was classified as likely benign. -

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
DEOGEN2	Benign	0.021	.;T;.
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;.
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;