rs34708681

chr4-150852021-C-Achr4-150852021-C-Gchr4-150852021-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364905.1(LRBA):c.3689G>T(p.Gly1230Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,814 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. G1230D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (1 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.764

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 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=0.055121303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.3689G>T	p.Gly1230Val	missense_variant	23/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.3689G>T	p.Gly1230Val	missense_variant	23/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251304 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135812

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461814 Hom.: 1 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	0.031
Dann	Benign	0.62
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.055	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.22	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.13
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.17
MPC		0.15
ClinPred		0.032	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.22

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: rs34708681; hg19: chr4-151773173;