rs17027154

Variant names:

• chr4-150867803-A-C
• rs17027154
• NM_001364905.1:c.2634T>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001364905.1(LRBA):​c.2634T>G​(p.Pro878Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,826 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (124 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (129 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.578
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 4-150867803-A-C is Benign according to our data. Variant chr4-150867803-A-C is described in ClinVar as Benign. ClinVar VariationId is 540403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.578 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.077 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364905.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	NM_001364905.1	MANE Select	c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.2634T>G	p.Pro878Pro	synonymous	Exon 22 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.0228 AC: 3475 AN: 152134 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.0794

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.00613 AC: 1540 AN: 251140 AF XY: 0.00441

Gnomad AFR exome AF: 0.0852

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00239 AC: 3489 AN: 1461574 Hom.: 129 Cov.: 31 AF XY: 0.00196 AC XY: 1425 AN XY: 727104

African (AFR) AF: 0.0841 AC: 2814 AN: 33470

American (AMR) AF: 0.00436 AC: 195 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.000138 AC: 153 AN: 1111828

Other (OTH) AF: 0.00494 AC: 298 AN: 60380

GnomAD4 genome AF: 0.0229 AC: 3480 AN: 152252 Hom.: 124 Cov.: 32 AF XY: 0.0222 AC XY: 1651 AN XY: 74462

African (AFR) AF: 0.0793 AC: 3293 AN: 41530

American (AMR) AF: 0.00830 AC: 127 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68016

Other (OTH) AF: 0.0194 AC: 41 AN: 2110

Alfa AF: 0.00866 Hom.: 36

Bravo AF: 0.0263

Asia WGS AF: 0.00462 AC: 16 AN: 3474

EpiCase AF: 0.0000546

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Combined immunodeficiency due to LRBA deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	6.6
DANN	Benign	0.76
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs17027154; hg19: chr4-151788955;