rs202244838
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_001364905.1(LRBA):c.8024C>T(p.Thr2675Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000951 in 1,566,416 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001364905.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LRBA | NM_001364905.1 | c.8024C>T | p.Thr2675Ile | missense_variant | 54/57 | ENST00000651943.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LRBA | ENST00000651943.2 | c.8024C>T | p.Thr2675Ile | missense_variant | 54/57 | NM_001364905.1 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.000638 AC: 97AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000431 AC: 78AN: 181042Hom.: 0 AF XY: 0.000406 AC XY: 39AN XY: 96090
GnomAD4 exome AF: 0.000985 AC: 1393AN: 1414270Hom.: 2 Cov.: 29 AF XY: 0.000933 AC XY: 653AN XY: 699858
GnomAD4 genome ? AF: 0.000638 AC: 97AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.000605 AC XY: 45AN XY: 74338
ClinVar
Submissions by phenotype
Combined immunodeficiency due to LRBA deficiency Uncertain:3Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | LRBA NM_006726.4 exon 55 p.Thr2686Ile (c.8057C>T): This variant has not been reported in the literature but is present in 0.08% (79/92680) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/4-151207180-G-A?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:497404). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 06-16-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 2686 of the LRBA protein (p.Thr2686Ile). This variant is present in population databases (rs202244838, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LRBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 497404). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 19, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 3C-VUS. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0112 - Variants in this gene are known to have reduced penetrance (PMID: 31432443, PMID: 28473463). (N) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine (exon 54). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0504 - Same amino acid change has been observed in a mammal. (N) 0600 - Variant is located in an annotated domain or motif (WD40 repeat; NCBI). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance (ClinVar) and as likely benign (LOVD). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1206 - Variant is paternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 10, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 10, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 16, 2022 | BP4 - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2021 | The c.8057C>T (p.T2686I) alteration is located in exon 55 (coding exon 54) of the LRBA gene. This alteration results from a C to T substitution at nucleotide position 8057, causing the threonine (T) at amino acid position 2686 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at