chr4-150415555-C-T

Position:

chr4-150415555-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001364905.1(LRBA):c.7077G>A(p.Met2359Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000622 in 1,591,468 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.16

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06659034).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1 link	c.7077G>A	p.Met2359Ile	missense_variant	47/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2 link	c.7077G>A	p.Met2359Ile	missense_variant	47/57		NM_001364905.1	ENSP00000498582.2		A0A494C1L5

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000997

AC:

AN:

250780

Hom.:

AF XY:

0.0000812

AC XY:

AN XY:

135534

show subpopulations

Gnomad AFR exome

AF:

0.00142

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000313

AC:

AN:

1439208

Hom.:

Cov.:

AF XY:

0.0000237

AC XY:

AN XY:

717602

show subpopulations

Gnomad4 AFR exome

AF:

0.00121

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000335

GnomAD4 genome

AF:

0.000355

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000378

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 12, 2022	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2370 of the LRBA protein (p.Met2370Ile). This variant is present in population databases (rs146268782, gnomAD 0.1%). 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: 540380). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.7110G>A (p.M2370I) alteration is located in exon 48 (coding exon 47) of the LRBA gene. This alteration results from a G to A substitution at nucleotide position 7110, causing the methionine (M) at amino acid position 2370 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

.;T;.;.;.

Eigen

Benign

0.073

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.067

T;T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.1

.;M;.;.;.

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.9

D;D;.;D;.

REVEL

Uncertain

0.41

Sift

Benign

0.074

T;T;.;T;.

Sift4G

Benign

0.11

T;T;.;T;.

Polyphen

0.018

B;B;.;.;.

Vest4

0.29

MutPred

0.52

.;Gain of sheet (P = 0.0477);.;.;.;

MVP

0.61

MPC

0.58

ClinPred

0.14

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.58

gMVP

0.78

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