rs908422044

Variant names:

• chr4-150597103-T-C
• rs908422044
• ENST00000357115.9:c.6059A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001440430.1(LRBA):​c.6059A>G​(p.Lys2020Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,251,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: LRBA NM_001440430.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.728
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08502826).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440430.1. 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.6046+1904A>G		intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.6059A>G	p.Lys2020Arg	missense	Exon 39 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.6059A>G	p.Lys2020Arg	missense	Exon 39 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000357115.9	TSL:1	c.6059A>G	p.Lys2020Arg	missense	Exon 39 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000651943.2	MANE Select	c.6046+1904A>G		intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000510413.5	TSL:1	c.6046+1904A>G		intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1251620 Hom.: 0 Cov.: 18 AF XY: 0.00000318 AC XY: 2 AN XY: 628838

African (AFR) AF: 0.00 AC: 0 AN: 27992

American (AMR) AF: 0.00 AC: 0 AN: 37942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35812

South Asian (SAS) AF: 0.00 AC: 0 AN: 72894

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51772

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5328

European-Non Finnish (NFE) AF: 0.00000212 AC: 2 AN: 943392

Other (OTH) AF: 0.00 AC: 0 AN: 52476

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Combined immunodeficiency due to LRBA deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.73
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.021
Sift	Benign	0.35	T
Sift4G	Benign	0.50	T
Polyphen		0.077	B
Vest4		0.15
MutPred		0.42		Loss of ubiquitination at K2020 (P = 0.0098)
MVP		0.23
MPC		0.093
ClinPred		0.062	T
GERP RS		2.5
Varity_R		0.026
gMVP		0.24
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs908422044; hg19: chr4-151518255;