rs143754610

Variant names:

• chr4-150905994-C-A
• rs143754610
• NM_001364905.1:c.1603-4G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001364905.1(LRBA):​c.1603-4G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.01 in 1,608,056 control chromosomes in the GnomAD database, including 694 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (136 hom., cov: 31)
  • Exomes 𝑓: 0.0093 (558 hom.)
• Consequence: LRBA NM_001364905.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001193
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.430
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 4-150905994-C-A is Benign according to our data. Variant chr4-150905994-C-A is described in ClinVar as Benign. ClinVar VariationId is 473168.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.053 is higher than 0.05.

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.1603-4G>T		splice_region intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.1603-4G>T		splice_region intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.1603-4G>T		splice_region intron	N/A	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.1603-4G>T		splice_region intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.1603-4G>T		splice_region intron	N/A	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.1603-4G>T		splice_region intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2626 AN: 151734 Hom.: 135 Cov.: 31

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0560

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0482

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00311

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0281 AC: 6925 AN: 246602 AF XY: 0.0244

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.0890

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0533

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.00925 AC: 13473 AN: 1456204 Hom.: 558 Cov.: 30 AF XY: 0.00873 AC XY: 6322 AN XY: 724400

African (AFR) AF: 0.00121 AC: 40 AN: 33088

American (AMR) AF: 0.0883 AC: 3855 AN: 43672

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25918

East Asian (EAS) AF: 0.0496 AC: 1963 AN: 39592

South Asian (SAS) AF: 0.000985 AC: 84 AN: 85272

European-Finnish (FIN) AF: 0.104 AC: 5557 AN: 53296

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5728

European-Non Finnish (NFE) AF: 0.00125 AC: 1386 AN: 1109524

Other (OTH) AF: 0.00970 AC: 583 AN: 60114

GnomAD4 genome AF: 0.0173 AC: 2627 AN: 151852 Hom.: 136 Cov.: 31 AF XY: 0.0232 AC XY: 1723 AN XY: 74186

African (AFR) AF: 0.00162 AC: 67 AN: 41434

American (AMR) AF: 0.0561 AC: 856 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0477 AC: 247 AN: 5174

South Asian (SAS) AF: 0.00354 AC: 17 AN: 4802

European-Finnish (FIN) AF: 0.115 AC: 1201 AN: 10474

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

European-Non Finnish (NFE) AF: 0.00311 AC: 211 AN: 67928

Other (OTH) AF: 0.0133 AC: 28 AN: 2112

Alfa AF: 0.00490 Hom.: 4

Bravo AF: 0.0132

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.49
PhyloP100		-0.43
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.0
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: rs143754610; hg19: chr4-151827146; COSMIC: COSV63956050;