rs79392371

Variant names:

• chr4-150871372-T-C
• rs79392371
• NM_001364905.1:c.2340A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001440430.1(LRBA):​c.2340A>G​(p.Thr780Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,610,266 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: LRBA NM_001440430.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.834
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 4-150871372-T-C is Benign according to our data. Variant chr4-150871372-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289382.
• BP7: Synonymous conserved (PhyloP=0.834 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00117 (178/152320) while in subpopulation NFE AF = 0.0021 (143/68032). AF 95% confidence interval is 0.00182. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	NM_001364905.1	MANE Select	c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 58	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.2340A>G	p.Thr780Thr	synonymous	Exon 19 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.00117 AC: 178 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000699

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00210

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00102 AC: 255 AN: 251098 AF XY: 0.000973

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00238 AC: 3465 AN: 1457946 Hom.: 8 Cov.: 28 AF XY: 0.00231 AC XY: 1673 AN XY: 725476

African (AFR) AF: 0.000389 AC: 13 AN: 33418

American (AMR) AF: 0.000224 AC: 10 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86038

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53344

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

European-Non Finnish (NFE) AF: 0.00304 AC: 3373 AN: 1108752

Other (OTH) AF: 0.000897 AC: 54 AN: 60220

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74478

African (AFR) AF: 0.000697 AC: 29 AN: 41584

American (AMR) AF: 0.000131 AC: 2 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00210 AC: 143 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00104

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Combined immunodeficiency due to LRBA deficiency (2)
-	-	1	LRBA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		0.83
PromoterAI		0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs79392371; hg19: chr4-151792524;