rs17027133

Variant names:

• chr4-150828321-T-C
• rs17027133
• NM_001364905.1:c.5030A>G

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.5030A>G​(p.Asn1677Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000873 in 1,614,168 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N1677N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: LRBA NM_001440430.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 5.76
• Publications: 5 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=0.009606034).
• BP6: Variant 4-150828321-T-C is Benign according to our data. Variant chr4-150828321-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540408.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00333 (508/152342) while in subpopulation AFR AF = 0.0107 (446/41582). AF 95% confidence interval is 0.0099. There are 2 homozygotes in GnomAd4. There are 221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.5030A>G	p.Asn1677Ser	missense	Exon 30 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.5030A>G	p.Asn1677Ser	missense	Exon 30 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.5030A>G	p.Asn1677Ser	missense	Exon 30 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.5030A>G	p.Asn1677Ser	missense	Exon 30 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.5030A>G	p.Asn1677Ser	missense	Exon 30 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.5030A>G	p.Asn1677Ser	missense	Exon 30 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152224 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00113 AC: 284 AN: 251350 AF XY: 0.000994

Gnomad AFR exome AF: 0.0100

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00120

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000616 AC: 901 AN: 1461826 Hom.: 1 Cov.: 32 AF XY: 0.000627 AC XY: 456 AN XY: 727214

African (AFR) AF: 0.0122 AC: 408 AN: 33478

American (AMR) AF: 0.000515 AC: 23 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00229 AC: 91 AN: 39694

South Asian (SAS) AF: 0.00154 AC: 133 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000133 AC: 148 AN: 1111980

Other (OTH) AF: 0.00136 AC: 82 AN: 60396

GnomAD4 genome AF: 0.00333 AC: 508 AN: 152342 Hom.: 2 Cov.: 32 AF XY: 0.00297 AC XY: 221 AN XY: 74504

African (AFR) AF: 0.0107 AC: 446 AN: 41582

American (AMR) AF: 0.00124 AC: 19 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5182

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00142 Hom.: 4

Bravo AF: 0.00338

ESP6500AA AF: 0.00999 AC: 44

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00128 AC: 155

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Combined immunodeficiency due to LRBA deficiency (3)
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	1	LRBA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	-0.052	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.014	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.36
MVP		0.73
MPC		0.49
ClinPred		0.050	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.35
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17027133; hg19: chr4-151749473;