rs62346982

chr4-150321257-T-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.7564A>C(p.Thr2522Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,612,060 control chromosomes in the GnomAD database, including 52 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (52 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.458

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=0.008562565).
• BP6: Variant 4-150321257-T-G is Benign according to our data. Variant chr4-150321257-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 439869.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=5, Uncertain_significance=1}. Variant chr4-150321257-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (679/152124) while in subpopulation NFE AF= 0.00799 (543/67990). AF 95% confidence interval is 0.00743. There are 0 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.7564A>C	p.Thr2522Pro	missense_variant	50/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.7564A>C	p.Thr2522Pro	missense_variant	50/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 679 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00799

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00424 AC: 1051 AN: 248108 Hom.: 6 AF XY: 0.00408 AC XY: 548 AN XY: 134150

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000688

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000134

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00725 AC: 10581 AN: 1459936 Hom.: 52 Cov.: 31 AF XY: 0.00701 AC XY: 5092 AN XY: 726282

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.000815

Gnomad4 ASJ exome AF: 0.00180

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00227

Gnomad4 NFE exome AF: 0.00906

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74374

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00223

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00189

Gnomad4 NFE AF: 0.00799

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00701 Hom.: 4

Bravo AF: 0.00487

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00463 AC: 562

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00721

EpiControl AF: 0.00689

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 18, 2020	BS1, BP4 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Oct 04, 2022	This variant has been reported in the literature in 1 individual with panuveitis (Li 2021 PMID:32707200). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.7% (543/67998) (https://gnomad.broadinstitute.org/variant/4-150321257-T-G?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:439869). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant suggests that this variant does not cause disease but requires further evidence. Therefore, this variant is classified as likely benign. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 22, 2017	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

LRBA: BP4, BS2 -

LRBA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Benign	0.96
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T;T;T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0086	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	N;N;.;N;.
REVEL	Benign	0.24
Sift	Benign	0.14	T;T;.;T;.
Sift4G	Benign	0.22	T;T;.;T;.
Polyphen		0.13	B;B;.;.;.
Vest4		0.43
MVP		0.44
MPC		0.18
ClinPred		0.0060	T
GERP RS		2.3
Varity_R		0.32
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs62346982; hg19: chr4-151242409;