rs34662958

Variant names:

• chr4-150285946-C-G
• rs34662958
• NM_001364905.1:c.8106G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001364905.1(LRBA):​c.8106G>C​(p.Leu2702Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,579,550 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L2702M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (22 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.414
• 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: Genomics England PanelApp, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008568227).
• BP6: Variant 4-150285946-C-G is Benign according to our data. Variant chr4-150285946-C-G is described in ClinVar as Benign. ClinVar VariationId is 473189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0103 (1568/152262) while in subpopulation AFR AF = 0.0359 (1491/41518). AF 95% confidence interval is 0.0344. There are 24 homozygotes in GnomAd4. There are 714 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.8106G>C	p.Leu2702Phe	missense	Exon 54 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.8154G>C	p.Leu2718Phe	missense	Exon 55 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.8139G>C	p.Leu2713Phe	missense	Exon 55 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.8106G>C	p.Leu2702Phe	missense	Exon 54 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.8139G>C	p.Leu2713Phe	missense	Exon 55 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.8103G>C	p.Leu2701Phe	missense	Exon 54 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1564 AN: 152144 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00287 AC: 604 AN: 210292 AF XY: 0.00227

Gnomad AFR exome AF: 0.0377

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000309

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00102 AC: 1457 AN: 1427288 Hom.: 22 Cov.: 29 AF XY: 0.000911 AC XY: 645 AN XY: 708058

African (AFR) AF: 0.0351 AC: 1135 AN: 32306

American (AMR) AF: 0.00260 AC: 96 AN: 36934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25374

East Asian (EAS) AF: 0.00 AC: 0 AN: 37752

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79358

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52368

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5722

European-Non Finnish (NFE) AF: 0.0000382 AC: 42 AN: 1098380

Other (OTH) AF: 0.00279 AC: 165 AN: 59094

GnomAD4 genome AF: 0.0103 AC: 1568 AN: 152262 Hom.: 24 Cov.: 33 AF XY: 0.00959 AC XY: 714 AN XY: 74464

African (AFR) AF: 0.0359 AC: 1491 AN: 41518

American (AMR) AF: 0.00373 AC: 57 AN: 15298

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68026

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00172 Hom.: 5

Bravo AF: 0.0119

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00331 AC: 402

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.41
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.71	P
Vest4		0.52
MutPred		0.20		Gain of glycosylation at S2714 (P = 0.0771)
MVP		0.12
MPC		0.57
ClinPred		0.034	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.50
Mutation Taster		=99/1	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: rs34662958; hg19: chr4-151207098;