chr4-150914350-GA-G

Variant names:

• chr4-150914350-GA-G
• rs753223643
• NM_001364905.1:c.1015-10delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000651943.2(LRBA):​c.1015-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 858,622 control chromosomes in the GnomAD database, including 46 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (26 hom., cov: 32)
  • Exomes 𝑓: 0.051 (20 hom.)
• Consequence: LRBA ENST00000651943.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.262
• 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 -16 ACMG points.

• BP6: Variant 4-150914350-GA-G is Benign according to our data. Variant chr4-150914350-GA-G is described in ClinVar as Benign. ClinVar VariationId is 522233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000651943.2. 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.1015-10delT		intron	N/A	NP_001351834.1
	LRBA	NM_001440430.1		c.1015-10delT		intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.1015-10delT		intron	N/A	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.1015-10delT		intron	N/A	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.1015-10delT		intron	N/A	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.1015-10delT		intron	N/A	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 1591 AN: 99488 Hom.: 26 Cov.: 32

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00490

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000558

Gnomad SAS AF: 0.000932

Gnomad FIN AF: 0.00326

Gnomad MID AF: 0.00472

Gnomad NFE AF: 0.000835

Gnomad OTH AF: 0.0131

GnomAD2 exomes AF: 0.152 AC: 9314 AN: 61426 AF XY: 0.156

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.208

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.0729

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.0514 AC: 38999 AN: 759126 Hom.: 20 Cov.: 20 AF XY: 0.0536 AC XY: 19681 AN XY: 367254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.106 AC: 1791 AN: 16966

American (AMR) AF: 0.0987 AC: 1294 AN: 13108

Ashkenazi Jewish (ASJ) AF: 0.0763 AC: 811 AN: 10630

East Asian (EAS) AF: 0.0737 AC: 1299 AN: 17616

South Asian (SAS) AF: 0.0941 AC: 2827 AN: 30036

European-Finnish (FIN) AF: 0.0614 AC: 1517 AN: 24692

Middle Eastern (MID) AF: 0.0347 AC: 108 AN: 3114

European-Non Finnish (NFE) AF: 0.0449 AC: 27561 AN: 613594

Other (OTH) AF: 0.0610 AC: 1791 AN: 29370

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0160 AC: 1592 AN: 99496 Hom.: 26 Cov.: 32 AF XY: 0.0152 AC XY: 736 AN XY: 48464

African (AFR) AF: 0.0528 AC: 1461 AN: 27664

American (AMR) AF: 0.00480 AC: 49 AN: 10200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2210

East Asian (EAS) AF: 0.000560 AC: 2 AN: 3572

South Asian (SAS) AF: 0.00125 AC: 4 AN: 3196

European-Finnish (FIN) AF: 0.00326 AC: 20 AN: 6144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.000858 AC: 38 AN: 44306

Other (OTH) AF: 0.0130 AC: 18 AN: 1386

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.0116

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Combined immunodeficiency due to LRBA deficiency (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
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: rs753223643; hg19: chr4-151835502;