rs138428438

Variant names:

• chr4-150590743-C-T
• rs138428438
• NM_001364905.1:c.6163G>A

Your query was ambiguous. Multiple possible variants found:

• chr4-150590743-C-T
• chr4-150590743-C-A

Variant summary

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

The NM_001364905.1(LRBA):​c.6163G>A​(p.Val2055Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000228 in 1,613,866 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (3 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.679
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005570084).
• BP6: Variant 4-150590743-C-T is Benign according to our data. Variant chr4-150590743-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473182.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000249 (38/152310) while in subpopulation EAS AF = 0.00638 (33/5174). AF 95% confidence interval is 0.00467. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.6163G>A	p.Val2055Met	missense	Exon 39 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.6196G>A	p.Val2066Met	missense	Exon 40 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.6196G>A	p.Val2066Met	missense	Exon 40 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.6163G>A	p.Val2055Met	missense	Exon 39 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.6196G>A	p.Val2066Met	missense	Exon 40 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.6163G>A	p.Val2055Met	missense	Exon 39 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00636

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000633 AC: 159 AN: 251008 AF XY: 0.000568

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00806

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000226 AC: 330 AN: 1461556 Hom.: 3 Cov.: 30 AF XY: 0.000237 AC XY: 172 AN XY: 727062

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00723 AC: 287 AN: 39680

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86188

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111828

Other (OTH) AF: 0.000149 AC: 9 AN: 60386

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152310 Hom.: 0 Cov.: 31 AF XY: 0.000228 AC XY: 17 AN XY: 74482

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15294

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

East Asian (EAS) AF: 0.00638 AC: 33 AN: 5174

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000348

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000700 AC: 85

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to LRBA deficiency (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.68
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.099
Sift	Benign	0.15	T
Sift4G	Benign	0.090	T
Polyphen		0.026	B
Vest4		0.27
MVP		0.33
MPC		0.12
ClinPred		0.026	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.032
gMVP		0.15
Mutation Taster		=89/11	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: rs138428438; hg19: chr4-151511895; COSMIC: COSV63964539;