4-151014529-C-A

Variant names:

• chr4-151014529-C-A
• rs72721739
• NM_001364905.1:c.114G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001364905.1(LRBA):​c.114G>T​(p.Gly38Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,614,090 control chromosomes in the GnomAD database, including 4 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. G38G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.0500
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP6: Variant 4-151014529-C-A is Benign according to our data. Variant chr4-151014529-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 425341.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00111 (169/152354) while in subpopulation NFE AF = 0.00168 (114/68032). AF 95% confidence interval is 0.00143. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.114G>T	p.Gly38Gly	synonymous	Exon 2 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.114G>T	p.Gly38Gly	synonymous	Exon 2 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.114G>T	p.Gly38Gly	synonymous	Exon 2 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.114G>T	p.Gly38Gly	synonymous	Exon 2 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.114G>T	p.Gly38Gly	synonymous	Exon 2 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.114G>T	p.Gly38Gly	synonymous	Exon 2 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00121 AC: 305 AN: 251130 AF XY: 0.00121

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00165

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00152 AC: 2227 AN: 1461736 Hom.: 4 Cov.: 30 AF XY: 0.00149 AC XY: 1083 AN XY: 727148

African (AFR) AF: 0.000269 AC: 9 AN: 33478

American (AMR) AF: 0.00130 AC: 58 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00344 AC: 90 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86206

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53396

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00170 AC: 1895 AN: 1111952

Other (OTH) AF: 0.00179 AC: 108 AN: 60394

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74496

African (AFR) AF: 0.000289 AC: 12 AN: 41580

American (AMR) AF: 0.00137 AC: 21 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00102 Hom.: 0

Bravo AF: 0.00114

Asia WGS AF: 0.00144 AC: 6 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	Combined immunodeficiency due to LRBA deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.83
PhyloP100		-0.050
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs72721739; hg19: chr4-151935681;