rs145690847

Variant names:

• chr4-150265764-G-A
• rs145690847
• NM_001364905.1:c.8517C>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_001364905.1(LRBA):​c.8517C>T​(p.Asn2839Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,598 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: LRBA NM_001364905.1 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.250

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 4-150265764-G-A is Benign according to our data. Variant chr4-150265764-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 724342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.25 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.8517C>T	p.Asn2839Asn	synonymous_variant	Exon 57 of 57	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.8517C>T	p.Asn2839Asn	synonymous_variant	Exon 57 of 57		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152092 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000164 AC: 41 AN: 249244 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 134916

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1461388 Hom.: 0 Cov.: 29 AF XY: 0.0000674 AC XY: 49 AN XY: 727050

Gnomad4 AFR exome AF: 0.000777

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.000417 AC XY: 31 AN XY: 74412

Gnomad4 AFR AF: 0.00116

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.000298

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:1

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jul 21, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jun 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	2.2
DANN	Benign	0.95
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.71	D
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs145690847; hg19: chr4-151186916;