rs116526975
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_001364905.1(LRBA):c.6662T>C(p.Ile2221Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,555,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000076 ( 0 hom. )
Consequence
LRBA
NM_001364905.1 missense
NM_001364905.1 missense
Scores
4
10
3
Clinical Significance
Conservation
PhyloP100: 9.30
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 Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.03741923).
BP6
?
Variant 4-150471629-A-G is Benign according to our data. Variant chr4-150471629-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 567653.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
?
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000795 (121/152240) while in subpopulation AFR AF= 0.00248 (103/41584). AF 95% confidence interval is 0.00209. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRBA | NM_001364905.1 | c.6662T>C | p.Ile2221Thr | missense_variant | 43/57 | ENST00000651943.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRBA | ENST00000651943.2 | c.6662T>C | p.Ile2221Thr | missense_variant | 43/57 | NM_001364905.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000795 AC: 121AN: 152122Hom.: 0 Cov.: 32
GnomAD3 genomes
?
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GnomAD3 exomes AF: 0.000166 AC: 39AN: 235218Hom.: 0 AF XY: 0.0000943 AC XY: 12AN XY: 127268
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GnomAD4 exome AF: 0.0000756 AC: 106AN: 1402864Hom.: 0 Cov.: 24 AF XY: 0.0000856 AC XY: 60AN XY: 700606
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GnomAD4 genome ? AF: 0.000795 AC: 121AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000779 AC XY: 58AN XY: 74430
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ESP6500AA
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 23, 2020 | - - |
Combined immunodeficiency due to LRBA deficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;.;D
REVEL
Pathogenic
Sift
Uncertain
D;D;.;D
Sift4G
Pathogenic
D;D;.;D
Polyphen
B;P;.;.
Vest4
MVP
MPC
0.40
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at