4-150321257-T-C

Variant names:

• chr4-150321257-T-C
• rs62346982
• NM_001364905.1:c.7564A>G

Variant summary

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

The NM_001364905.1(LRBA):​c.7564A>G​(p.Thr2522Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. T2522P) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458
• 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: 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=0.10385805).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	NM_001364905.1	MANE Select	c.7564A>G	p.Thr2522Ala	missense	Exon 50 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.7612A>G	p.Thr2538Ala	missense	Exon 51 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.7597A>G	p.Thr2533Ala	missense	Exon 51 of 58	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.7564A>G	p.Thr2522Ala	missense	Exon 50 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.7597A>G	p.Thr2533Ala	missense	Exon 51 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.7564A>G	p.Thr2522Ala	missense	Exon 50 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459950 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726292

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.00 AC: 0 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111422

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	9.9
DANN	Benign	0.90
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0094	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.46
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Benign	0.39	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.25
MutPred		0.59		Loss of sheet (P = 0.0817)
MVP		0.34
MPC		0.11
ClinPred		0.046	T
GERP RS		2.3
Varity_R		0.055
gMVP		0.11
Mutation Taster		=98/2	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: rs62346982; hg19: chr4-151242409;