rs62344598

Positions:

• chr4-150914212-A-G
• chr4-150914212-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001364905.1(LRBA):​c.1144T>C​(p.Leu382=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.038 in 1,607,730 control chromosomes in the GnomAD database, including 2,277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L382L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.075 (810 hom., cov: 31)
  • Exomes 𝑓: 0.034 (1467 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.93

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 4-150914212-A-G is Benign according to our data. Variant chr4-150914212-A-G is described in ClinVar as [Benign]. Clinvar id is 473165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150914212-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.93 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRBA	NM_001364905.1	c.1144T>C	p.Leu382=	synonymous_variant	9/57	ENST00000651943.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRBA	ENST00000651943.2	c.1144T>C	p.Leu382=	synonymous_variant	9/57		NM_001364905.1	P3

Frequencies

GnomAD3 genomes AF: 0.0751 AC: 11412 AN: 151928 Hom.: 803 Cov.: 31

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0355

Gnomad ASJ AF: 0.0403

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0325

Gnomad OTH AF: 0.0594

GnomAD3 exomes AF: 0.0393 AC: 9808 AN: 249438 Hom.: 437 AF XY: 0.0361 AC XY: 4875 AN XY: 134900

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.0000551

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.0384

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0380

GnomAD4 exome AF: 0.0341 AC: 49652 AN: 1455684 Hom.: 1467 Cov.: 31 AF XY: 0.0332 AC XY: 24036 AN XY: 724150

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0258

Gnomad4 ASJ exome AF: 0.0423

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0391

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0413

GnomAD4 genome AF: 0.0753 AC: 11446 AN: 152046 Hom.: 810 Cov.: 31 AF XY: 0.0732 AC XY: 5441 AN XY: 74352

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.0403

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0104

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0324

Gnomad4 OTH AF: 0.0588

Alfa AF: 0.0469 Hom.: 201

Bravo AF: 0.0827

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	6.4
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs62344598; hg19: chr4-151835364; COSMIC: COSV63950617;