4-150929074-G-T

Variant names:

• chr4-150929074-G-T
• rs1163872504
• NM_001364905.1:c.217-9C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001364905.1(LRBA):​c.217-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000272 in 1,101,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Scores: Splicing: ADA: 0.0008795
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.217-9C>A		intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.217-9C>A		intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.217-9C>A		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.217-9C>A		intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.217-9C>A		intron	N/A	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.217-9C>A		intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000272 AC: 3 AN: 1101840 Hom.: 0 Cov.: 22 AF XY: 0.00000182 AC XY: 1 AN XY: 549098

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

African (AFR) AF: 0.00 AC: 0 AN: 25604

American (AMR) AF: 0.00 AC: 0 AN: 30026

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19786

East Asian (EAS) AF: 0.00 AC: 0 AN: 30064

South Asian (SAS) AF: 0.00 AC: 0 AN: 62772

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4570

European-Non Finnish (NFE) AF: 0.00000237 AC: 2 AN: 845546

Other (OTH) AF: 0.00 AC: 0 AN: 45544

⚠️ 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 Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.23
PhyloP100		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00088
dbscSNV1_RF	Benign	0.084
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: rs1163872504; hg19: chr4-151850226;