NM_001364905.1:c.5550T>C

Variant names:

• chr4-150798111-A-G
• rs1129998
• NM_001364905.1:c.5550T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001364905.1(LRBA):​c.5550T>C​(p.Val1850Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,603,866 control chromosomes in the GnomAD database, including 41,972 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2905 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39067 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.44
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• combined immunodeficiency due to LRBA deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.1).
• BP6: Variant 4-150798111-A-G is Benign according to our data. Variant chr4-150798111-A-G is described in ClinVar as Benign. ClinVar VariationId is 403050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.44 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.5550T>C	p.Val1850Val	synonymous_variant	Exon 34 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.5550T>C	p.Val1850Val	synonymous_variant	Exon 34 of 57		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 26094 AN: 151932 Hom.: 2906 Cov.: 32

Gnomad AFR AF: 0.0431

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.197

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.183 AC: 46013 AN: 250976 AF XY: 0.186

Gnomad AFR exome AF: 0.0410

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.121

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.282

Gnomad NFE exome AF: 0.237

Gnomad OTH exome AF: 0.194

GnomAD4 exome AF: 0.223 AC: 324041 AN: 1451816 Hom.: 39067 Cov.: 28 AF XY: 0.220 AC XY: 159189 AN XY: 722694

African (AFR) AF: 0.0357 AC: 1192 AN: 33388

American (AMR) AF: 0.107 AC: 4761 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3150 AN: 26044

East Asian (EAS) AF: 0.187 AC: 7397 AN: 39556

South Asian (SAS) AF: 0.110 AC: 9432 AN: 85950

European-Finnish (FIN) AF: 0.282 AC: 15038 AN: 53312

Middle Eastern (MID) AF: 0.158 AC: 909 AN: 5748

European-Non Finnish (NFE) AF: 0.245 AC: 270248 AN: 1103112

Other (OTH) AF: 0.198 AC: 11914 AN: 60040

GnomAD4 genome AF: 0.172 AC: 26086 AN: 152050 Hom.: 2905 Cov.: 32 AF XY: 0.171 AC XY: 12680 AN XY: 74332

African (AFR) AF: 0.0430 AC: 1788 AN: 41536

American (AMR) AF: 0.145 AC: 2220 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 438 AN: 3468

East Asian (EAS) AF: 0.190 AC: 983 AN: 5180

South Asian (SAS) AF: 0.102 AC: 493 AN: 4810

European-Finnish (FIN) AF: 0.284 AC: 3006 AN: 10568

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16452 AN: 67910

Other (OTH) AF: 0.161 AC: 340 AN: 2110

Alfa AF: 0.207 Hom.: 9242

Bravo AF: 0.158

Asia WGS AF: 0.105 AC: 364 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 30% of patients studied by a panel of primary immunodeficiencies. Number of patients: 29. Only high quality variants are reported. -

not provided Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Combined immunodeficiency due to LRBA deficiency Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	7.4
DANN	Benign	0.74
PhyloP100		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1129998; hg19: chr4-151719263; COSMIC: COSV63953265;