chr4-150828289-T-C

Variant names:

• chr4-150828289-T-C
• rs746205437
• NM_001364905.1:c.5062A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001440430.1(LRBA):​c.5062A>G​(p.Ile1688Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1688L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LRBA NM_001440430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39
• Publications: 0 publications found

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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

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=0.08767834).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440430.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	NM_001364905.1	MANE Select	c.5062A>G	p.Ile1688Val	missense	Exon 30 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.5062A>G	p.Ile1688Val	missense	Exon 30 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.5062A>G	p.Ile1688Val	missense	Exon 30 of 58	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.5062A>G	p.Ile1688Val	missense	Exon 30 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.5062A>G	p.Ile1688Val	missense	Exon 30 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.5062A>G	p.Ile1688Val	missense	Exon 30 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to LRBA deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.071
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.10
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0070	B
Vest4		0.19
MutPred		0.32		Gain of disorder (P = 0.1126)
MVP		0.50
MPC		0.098
ClinPred		0.52	D
GERP RS		4.5
Varity_R		0.033
gMVP		0.12
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs746205437; hg19: chr4-151749441;