chr4-150798124-G-C

Variant names:

• chr4-150798124-G-C
• rs751188122
• NM_001364905.1:c.5537C>G

Variant summary

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

The NM_001364905.1(LRBA):​c.5537C>G​(p.Ser1846Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,566 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1846L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• 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.5537C>G	p.Ser1846Trp	missense	Exon 34 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.5537C>G	p.Ser1846Trp	missense	Exon 34 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.5537C>G	p.Ser1846Trp	missense	Exon 34 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.5537C>G	p.Ser1846Trp	missense	Exon 34 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.5537C>G	p.Ser1846Trp	missense	Exon 34 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.5537C>G	p.Ser1846Trp	missense	Exon 34 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454566 Hom.: 0 Cov.: 27 AF XY: 0.00000138 AC XY: 1 AN XY: 724074

African (AFR) AF: 0.00 AC: 0 AN: 33342

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105592

Other (OTH) AF: 0.00 AC: 0 AN: 60124

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.47		Loss of disorder (P = 5e-04)
MVP		0.82
MPC		0.53
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.49
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751188122; hg19: chr4-151719276;