rs72719663

Positions:

• chr4-150872751-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001364905.1(LRBA):​c.2170A>G​(p.Ile724Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 1,550,800 control chromosomes in the GnomAD database, including 615 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (42 hom., cov: 32)
  • Exomes 𝑓: 0.027 (573 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.09

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076279044).
• BP6: Variant 4-150872751-T-C is Benign according to our data. Variant chr4-150872751-T-C is described in ClinVar as [Benign]. Clinvar id is 473170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-150872751-T-C is described in Lovd as [Likely_benign]. Variant chr4-150872751-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0191 (2910/152228) while in subpopulation NFE AF= 0.0281 (1910/68000). AF 95% confidence interval is 0.027. There are 42 homozygotes in gnomad4. There are 1421 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 42 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.2170A>G	p.Ile724Val	missense_variant	18/57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.2170A>G	p.Ile724Val	missense_variant	18/57		NM_001364905.1	ENSP00000498582	P3

Frequencies

GnomAD3 genomes AF: 0.0191 AC: 2910 AN: 152110 Hom.: 42 Cov.: 32

Gnomad AFR AF: 0.00420

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.0165

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0281

Gnomad OTH AF: 0.0196

GnomAD3 exomes AF: 0.0212 AC: 5119 AN: 241228 Hom.: 91 AF XY: 0.0225 AC XY: 2934 AN XY: 130308

Gnomad AFR exome AF: 0.00438

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0281

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0238

Gnomad FIN exome AF: 0.0204

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0267 AC: 37287 AN: 1398572 Hom.: 573 Cov.: 23 AF XY: 0.0270 AC XY: 18841 AN XY: 698352

Gnomad4 AFR exome AF: 0.00393

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.0277

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.0251

Gnomad4 FIN exome AF: 0.0220

Gnomad4 NFE exome AF: 0.0293

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0191 AC: 2910 AN: 152228 Hom.: 42 Cov.: 32 AF XY: 0.0191 AC XY: 1421 AN XY: 74446

Gnomad4 AFR AF: 0.00416

Gnomad4 AMR AF: 0.0165

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0275

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.0281

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0260 Hom.: 82

Bravo AF: 0.0176

TwinsUK AF: 0.0318 AC: 118

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0306 AC: 263

ExAC AF: 0.0216 AC: 2629

Asia WGS AF: 0.00608 AC: 21 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.031	.;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.93	D;D;D
MetaRNN	Benign	0.0076	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.36	N;N;.
MutationTaster	Benign	0.75	D;D;D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.58	N;N;N
REVEL	Benign	0.052
Sift	Benign	0.39	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.097
MPC		0.095
ClinPred		0.011	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.034
gMVP		0.068

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

Publications

LitVar

Other links and lift over

dbSNP: rs72719663; hg19: chr4-151793903;