rs72719631

Positions:

• chr4-150817188-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001364905.1(LRBA):​c.5241T>C​(p.Asn1747Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,612,140 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (4 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.479

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 4-150817188-A-G is Benign according to our data. Variant chr4-150817188-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 425340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150817188-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.479 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00096 (146/152130) while in subpopulation NFE AF= 0.00153 (104/67918). AF 95% confidence interval is 0.00129. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.5241T>C	p.Asn1747Asn	synonymous_variant	31/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.5241T>C	p.Asn1747Asn	synonymous_variant	31/57		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes AF: 0.000960 AC: 146 AN: 152012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00112

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00106 AC: 265 AN: 250768 Hom.: 1 AF XY: 0.00103 AC XY: 140 AN XY: 135516

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000818

GnomAD4 exome AF: 0.00142 AC: 2070 AN: 1460010 Hom.: 4 Cov.: 30 AF XY: 0.00137 AC XY: 996 AN XY: 726362

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00349

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000187

Gnomad4 NFE exome AF: 0.00162

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.000960 AC: 146 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74396

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00112

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00153

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00101

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	LRBA: BP4, BP7 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Combined immunodeficiency due to LRBA deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.4
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs72719631; hg19: chr4-151738340;