rs151098394

Variant names:

• chr4-150867763-C-T
• rs151098394
• NM_001364905.1:c.2674G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001440430.1(LRBA):​c.2674G>A​(p.Ala892Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,613,450 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (4 hom.)
• Consequence: LRBA NM_001440430.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.43
• Publications: 8 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008976221).
• BP6: Variant 4-150867763-C-T is Benign according to our data. Variant chr4-150867763-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473172.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00434 (661/152202) while in subpopulation AFR AF = 0.0142 (589/41552). AF 95% confidence interval is 0.0132. There are 4 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440430.1. 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.2674G>A	p.Ala892Thr	missense	Exon 22 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.2674G>A	p.Ala892Thr	missense	Exon 22 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.2674G>A	p.Ala892Thr	missense	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.2674G>A	p.Ala892Thr	missense	Exon 22 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.2674G>A	p.Ala892Thr	missense	Exon 22 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.2674G>A	p.Ala892Thr	missense	Exon 22 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152084 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00479

GnomAD2 exomes AF: 0.00119 AC: 300 AN: 251260 AF XY: 0.000906

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000532 AC: 777 AN: 1461248 Hom.: 4 Cov.: 31 AF XY: 0.000472 AC XY: 343 AN XY: 726942

African (AFR) AF: 0.0133 AC: 445 AN: 33460

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5766

European-Non Finnish (NFE) AF: 0.000159 AC: 177 AN: 1111500

Other (OTH) AF: 0.00129 AC: 78 AN: 60372

GnomAD4 genome AF: 0.00434 AC: 661 AN: 152202 Hom.: 4 Cov.: 32 AF XY: 0.00422 AC XY: 314 AN XY: 74412

African (AFR) AF: 0.0142 AC: 589 AN: 41552

American (AMR) AF: 0.00288 AC: 44 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67998

Other (OTH) AF: 0.00474 AC: 10 AN: 2108

Alfa AF: 0.00180 Hom.: 2

Bravo AF: 0.00492

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00153 AC: 186

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.4
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.063
Sift	Benign	0.15	T
Sift4G	Benign	0.15	T
Polyphen		0.58	P
Vest4		0.44
MVP		0.63
MPC		0.24
ClinPred		0.0045	T
GERP RS		5.7
Varity_R		0.082
gMVP		0.27
Mutation Taster		=72/28	polymorphism

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: rs151098394; hg19: chr4-151788915; COSMIC: COSV100840750;