rs11735845

Variant names:

• chr4-150844184-G-A
• rs11735845
• NM_001364905.1:c.4485C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001364905.1(LRBA):​c.4485C>T​(p.Gly1495Gly) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G1495G) has been classified as Uncertain significance.

• 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:5
• Conservation: PhyloP100: -0.242
• Publications: 6 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BP6: Variant 4-150844184-G-A is Benign according to our data. Variant chr4-150844184-G-A is described in ClinVar as Benign. ClinVar VariationId is 403051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

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.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.4485C>T	p.Gly1495Gly	synonymous	Exon 28 of 57	ENSP00000421552.1	P50851-2

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

GnomAD2 exomes AF: 0.0206 AC: 5167 AN: 251252 AF XY: 0.0210

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 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

African (AFR) AF: 0.00504 AC: 168 AN: 33326

American (AMR) AF: 0.0151 AC: 674 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00689 AC: 179 AN: 25978

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39574

South Asian (SAS) AF: 0.00985 AC: 841 AN: 85348

European-Finnish (FIN) AF: 0.0268 AC: 1426 AN: 53170

Middle Eastern (MID) AF: 0.00802 AC: 46 AN: 5738

European-Non Finnish (NFE) AF: 0.0336 AC: 37066 AN: 1103714

Other (OTH) AF: 0.0258 AC: 1543 AN: 59912

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

African (AFR) AF: 0.00592 AC: 245 AN: 41382

American (AMR) AF: 0.0192 AC: 293 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00721 AC: 25 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00834 AC: 40 AN: 4796

European-Finnish (FIN) AF: 0.0271 AC: 283 AN: 10432

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2169 AN: 67914

Other (OTH) AF: 0.0200 AC: 42 AN: 2100

Alfa AF: 0.0280 Hom.: 106

Bravo AF: 0.0203

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.62
PhyloP100		-0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11735845; hg19: chr4-151765336;