rs199469663
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001364905.1(LRBA):āc.7937T>Gā(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 (ā ā ).
Frequency
Genomes: not found (cov: 32)
Exomes š: 0.0000034 ( 0 hom. )
Consequence
LRBA
NM_001364905.1 missense
NM_001364905.1 missense
Scores
11
4
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460970Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726788
GnomAD4 exome
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AC:
5
AN:
1460970
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Cov.:
30
AF XY:
AC XY:
2
AN XY:
726788
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;.
Polyphen
P;D;.
Vest4
MutPred
0.81
.;Gain of disorder (P = 0.0065);.;
MVP
MPC
0.58
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at