4-150436793-T-G

Variant names:

• chr4-150436793-T-G
• rs140538555
• NM_001364905.1:c.6852A>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_001364905.1(LRBA):​c.6852A>C​(p.Gln2284His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2284E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.667
• Publications: 4 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.30959278).

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.6852A>C	p.Gln2284His	missense	Exon 45 of 57	NP_001351834.1
	LRBA	NM_001440430.1		c.6885A>C	p.Gln2295His	missense	Exon 46 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.6885A>C	p.Gln2295His	missense	Exon 46 of 58	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.6852A>C	p.Gln2284His	missense	Exon 45 of 57	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.6885A>C	p.Gln2295His	missense	Exon 46 of 58	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.6852A>C	p.Gln2284His	missense	Exon 45 of 57	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

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: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 31 AN: 250924 AF XY: 0.000103

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000387 AC: 565 AN: 1461464 Hom.: 0 Cov.: 31 AF XY: 0.000366 AC XY: 266 AN XY: 727014

African (AFR) AF: 0.0000598 AC: 2 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39656

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000490 AC: 545 AN: 1111776

Other (OTH) AF: 0.000232 AC: 14 AN: 60368

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74330

African (AFR) AF: 0.0000965 AC: 4 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000230 Hom.: 1

Bravo AF: 0.000159

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 2295 of the LRBA protein (p.Gln2295His). This variant is present in population databases (rs140538555, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with LRBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 567991). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LRBA protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Inborn genetic diseases Uncertain:1

Aug 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6885A>C (p.Q2295H) alteration is located in exon 46 (coding exon 45) of the LRBA gene. This alteration results from a A to C substitution at nucleotide position 6885, causing the glutamine (Q) at amino acid position 2295 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.039	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.67
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.035	D
Sift4G	Benign	0.12	T
Polyphen		0.11	B
Vest4		0.44
MutPred		0.38		Gain of disorder (P = 0.0813)
MVP		0.61
MPC		0.11
ClinPred		0.23	T
GERP RS		3.5
PromoterAI		0.071	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.69
gMVP		0.70
Mutation Taster		=24/76	disease causing

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: rs140538555; hg19: chr4-151357945;