chr4-150844184-G-A

Position:

• chr4-150844184-G-A

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.4485C>T​(p.Gly1495=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0281 in 1,603,164 control chromosomes in the GnomAD database, including 803 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (51 hom., cov: 32)
  • Exomes 𝑓: 0.029 (752 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.242

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 4-150844184-G-A is Benign according to our data. Variant chr4-150844184-G-A is described in ClinVar as [Benign]. Clinvar id is 403051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150844184-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.242 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0208 (3159/151698) while in subpopulation NFE AF= 0.0319 (2169/67914). AF 95% confidence interval is 0.0308. There are 51 homozygotes in gnomad4. There are 1495 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.4485C>T	p.Gly1495=	synonymous_variant	28/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.4485C>T	p.Gly1495=	synonymous_variant	28/57		NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3158 AN: 151584 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00594

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0193

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00833

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0202

GnomAD3 exomes AF: 0.0206 AC: 5167 AN: 251252 Hom.: 82 AF XY: 0.0210 AC XY: 2849 AN XY: 135808

Gnomad AFR exome AF: 0.00610

Gnomad AMR exome AF: 0.0145

Gnomad ASJ exome AF: 0.00675

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00951

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0211

GnomAD4 exome AF: 0.0289 AC: 41946 AN: 1451466 Hom.: 752 Cov.: 30 AF XY: 0.0280 AC XY: 20252 AN XY: 722452

Gnomad4 AFR exome AF: 0.00504

Gnomad4 AMR exome AF: 0.0151

Gnomad4 ASJ exome AF: 0.00689

Gnomad4 EAS exome AF: 0.0000758

Gnomad4 SAS exome AF: 0.00985

Gnomad4 FIN exome AF: 0.0268

Gnomad4 NFE exome AF: 0.0336

Gnomad4 OTH exome AF: 0.0258

GnomAD4 genome AF: 0.0208 AC: 3159 AN: 151698 Hom.: 51 Cov.: 32 AF XY: 0.0202 AC XY: 1495 AN XY: 74070

Gnomad4 AFR AF: 0.00592

Gnomad4 AMR AF: 0.0192

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00834

Gnomad4 FIN AF: 0.0271

Gnomad4 NFE AF: 0.0319

Gnomad4 OTH AF: 0.0200

Alfa AF: 0.0259 Hom.: 35

Bravo AF: 0.0203

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, silent variant not in splice consensus -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11735845; hg19: chr4-151765336;