rs74366731

Variant names:

• chr4-150851870-A-C
• rs74366731
• NM_001364905.1:c.3825+15T>G

Your query was ambiguous. Multiple possible variants found:

• chr4-150851870-A-C
• chr4-150851870-A-G
• chr4-150851870-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001364905.1(LRBA):​c.3825+15T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000822 in 1,582,774 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.572
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 4-150851870-A-C is Benign according to our data. Variant chr4-150851870-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445852.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00459 (699/152320) while in subpopulation AFR AF = 0.0161 (668/41574). AF 95% confidence interval is 0.0151. There are 6 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.3825+15T>G		intron	N/A	NP_001351834.1
	LRBA	NM_001440430.1		c.3825+15T>G		intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.3825+15T>G		intron	N/A	NP_006717.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.3825+15T>G		intron	N/A	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.3825+15T>G		intron	N/A	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.3825+15T>G		intron	N/A	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.00462 AC: 703 AN: 152202 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

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: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00118 AC: 267 AN: 226416 AF XY: 0.000809

Gnomad AFR exome AF: 0.0152

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000192

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000421 AC: 602 AN: 1430454 Hom.: 3 Cov.: 30 AF XY: 0.000358 AC XY: 254 AN XY: 708914

African (AFR) AF: 0.0154 AC: 493 AN: 32116

American (AMR) AF: 0.00119 AC: 46 AN: 38698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24512

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.0000123 AC: 1 AN: 81096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52534

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5592

European-Non Finnish (NFE) AF: 0.00000638 AC: 7 AN: 1097556

Other (OTH) AF: 0.000898 AC: 53 AN: 59026

GnomAD4 genome AF: 0.00459 AC: 699 AN: 152320 Hom.: 6 Cov.: 32 AF XY: 0.00431 AC XY: 321 AN XY: 74474

African (AFR) AF: 0.0161 AC: 668 AN: 41574

American (AMR) AF: 0.00163 AC: 25 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.00549

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Combined immunodeficiency due to LRBA deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.6
DANN	Benign	0.44
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74366731; hg19: chr4-151773022;