4-150588056-C-T

Position:

chr4-150588056-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_001364905.1(LRBA):c.6322G>A(p.Asp2108Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000275 in 1,611,658 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 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 5.05

Variant links:

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]

LRBA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.022561938).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000271 (396/1459518) while in subpopulation AMR AF= 0.00218 (97/44438). AF 95% confidence interval is 0.00183. There are 0 homozygotes in gnomad4_exome. There are 182 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1 link	c.6322G>A	p.Asp2108Asn	missense_variant	40/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2 link	c.6322G>A	p.Asp2108Asn	missense_variant	40/57		NM_001364905.1	ENSP00000498582.2		A0A494C1L5

Frequencies

GnomAD3 genomes

AF:

0.000316

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000449

AC:

112

AN:

249394

Hom.:

AF XY:

0.000445

AC XY:

AN XY:

134758

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00229

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.000271

AC:

396

AN:

1459518

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

182

AN XY:

725936

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00218

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000351

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000253

Gnomad4 OTH exome

AF:

0.000249

GnomAD4 genome

AF:

0.000315

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000946

Bravo

AF:

0.000548

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 24, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2016	The D2119N variant in the LRBA gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the D2119N variant was observed with a frequency of 0.06% (5/8598 alleles) in individuals of European American ancestry in the NHLBI Exome Sequencing Project and with a frequency of 0.23% (27/11576 alleles) in individuals of Latino ancestry in the Exome Aggregation Consortium. The D2119N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals; however, Asparagine is observed at this position in two distantly related species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret D2119N as a variant of uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2021

The c.6355G>A (p.D2119N) alteration is located in exon 41 (coding exon 40) of the LRBA gene. This alteration results from a G to A substitution at nucleotide position 6355, causing the aspartic acid (D) at amino acid position 2119 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Combined immunodeficiency due to LRBA deficiency

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.28

.;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.023

T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.4

.;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Pathogenic

-4.8

D;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.026

D;D;D

Sift4G

Uncertain

0.050

T;T;T

Polyphen

0.23

B;B;.

Vest4

0.42

MVP

0.55

MPC

0.53

ClinPred

0.13

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over