4-150914350-GAAA-GAAAAA

Variant names:

• chr4-150914350-G-GAA
• rs753223643
• NM_001364905.1:c.1015-11_1015-10dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001364905.1(LRBA):​c.1015-11_1015-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000627 in 1,020,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Clinical Significance: Not reported in ClinVar
• 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1015-11_1015-10dupTT		intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.1015-11_1015-10dupTT		intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.1015-11_1015-10dupTT		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.1015-10_1015-9insTT		intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.1015-10_1015-9insTT		intron	N/A	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.1015-10_1015-9insTT		intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.0000100 AC: 1 AN: 99642 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000244 AC: 15 AN: 61426 AF XY: 0.000356

Gnomad AFR exome AF: 0.000420

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.000505

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000684 AC: 63 AN: 921062 Hom.: 0 Cov.: 20 AF XY: 0.0000825 AC XY: 37 AN XY: 448590

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

African (AFR) AF: 0.000243 AC: 5 AN: 20552

American (AMR) AF: 0.000113 AC: 2 AN: 17678

Ashkenazi Jewish (ASJ) AF: 0.0000717 AC: 1 AN: 13952

East Asian (EAS) AF: 0.0000402 AC: 1 AN: 24890

South Asian (SAS) AF: 0.000165 AC: 6 AN: 36390

European-Finnish (FIN) AF: 0.000123 AC: 4 AN: 32448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3682

European-Non Finnish (NFE) AF: 0.0000571 AC: 42 AN: 734986

Other (OTH) AF: 0.0000548 AC: 2 AN: 36484

⚠️ 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: 0.0000100 AC: 1 AN: 99642 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 48520

African (AFR) AF: 0.0000362 AC: 1 AN: 27632

American (AMR) AF: 0.00 AC: 0 AN: 10212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2220

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00 AC: 0 AN: 3218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 44396

Other (OTH) AF: 0.00 AC: 0 AN: 1376

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26

Splicing

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

Other links and lift over

dbSNP: rs753223643; hg19: chr4-151835502;