rs199469663

Positions:

• chr4-150302705-A-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001364905.1(LRBA):​c.7937T>G​(p.Ile2646Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915
• PP5: Variant 4-150302705-A-C is Pathogenic according to our data. Variant chr4-150302705-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 35455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.7937T>G	p.Ile2646Ser	missense_variant	53/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.7937T>G	p.Ile2646Ser	missense_variant	53/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460970 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The variant c.7970T>G (p.Ile2657Ser) in LRBA gene has been previously reported in individuals with early-onset immune deficiency and autoimmunity (LopezHerrera G et al, Revel-Vilk S et al). This variant has been reported to the ClinVar database as Pathogenic. The amino acid Ile at position 2657 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. This sequence change replaces isoleucine with serine at codon 2657 of the LRBA protein (p.Ile2657Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine. The residue is conserved across species. The variant is predicted to be damaging by both SIFT and PolyPhen2. The amino acid change p.Ile2657Ser in LRBA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Ile2657Ser variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 08, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 22, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects LRBA function (PMID: 22608502, 25931386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRBA protein function. ClinVar contains an entry for this variant (Variation ID: 35455). This variant is also known as c.7937T>G: p.I2646S. This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2657 of the LRBA protein (p.Ile2657Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with early-onset immune deficiency and autoimmunity (PMID: 22608502, 25931386, 28197149). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.079	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;D;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		0.69	P;D;.
Vest4		0.93
MutPred		0.81		.;Gain of disorder (P = 0.0065);.;
MVP		0.83
MPC		0.58
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.87

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: rs199469663; hg19: chr4-151223857;