Genetic Variant NM_001364905.1:c.3721A>G (chr4-150851989-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001364905.1(LRBA):c.3721A>G(p.Ile1241Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1241F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

LRBA
NM_001364905.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.50

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

combined immunodeficiency due to LRBA deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

LRBA links:

ENSG00000298996 (HGNC:):

ENSG00000298996 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2003845).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364905.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRBA	NM_001364905.1	MANE Select	c.3721A>G	p.Ile1241Val	missense	Exon 23 of 57	NP_001351834.1	A0A494C1L5
LRBA	NM_001440430.1		c.3721A>G	p.Ile1241Val	missense	Exon 23 of 58	NP_001427359.1
LRBA	NM_006726.5		c.3721A>G	p.Ile1241Val	missense	Exon 23 of 58	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LRBA	ENST00000651943.2	MANE Select	c.3721A>G	p.Ile1241Val	missense	Exon 23 of 57	ENSP00000498582.2	A0A494C1L5
LRBA	ENST00000357115.9	TSL:1	c.3721A>G	p.Ile1241Val	missense	Exon 23 of 58	ENSP00000349629.3	P50851-1
LRBA	ENST00000510413.5	TSL:1	c.3721A>G	p.Ile1241Val	missense	Exon 23 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.0095

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

M_CAP

Benign

0.0093

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.3

PhyloP100

7.5

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-0.20

REVEL

Benign

0.095

Sift

Benign

0.62

Sift4G

Benign

0.74

Polyphen

0.53

Vest4

0.38

MVP

0.47

MPC

0.48

ClinPred

0.92

GERP RS

5.8

Varity_R

0.046

gMVP

0.26

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over