rs746205437

Positions:

• chr4-150828289-T-C
• chr4-150828289-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001364905.1(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. 14/21 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_001364905.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08767834).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.5062A>G	p.Ile1688Val	missense_variant	30/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.5062A>G	p.Ile1688Val	missense_variant	30/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;D;D
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.21	N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0070	B;B;.
Vest4		0.19
MutPred		0.32		Gain of disorder (P = 0.1126);Gain of disorder (P = 0.1126);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

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: rs746205437; hg19: chr4-151749441;