NM_001364905.1:c.1015-10dupT

Variant names:

• chr4-150914350-G-GA
• rs753223643
• NM_001364905.1:c.1015-10dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001364905.1(LRBA):​c.1015-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0318 in 921,400 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.035 (7 hom.)
• Consequence: LRBA NM_001364905.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 0.262
• 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 -10 ACMG points.

• BP6: Variant 4-150914350-G-GA is Benign according to our data. Variant chr4-150914350-G-GA is described in ClinVar as Benign. ClinVar VariationId is 473164.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00497 (495/99596) while in subpopulation AMR AF = 0.00666 (68/10214). AF 95% confidence interval is 0.00539. There are 0 homozygotes in GnomAd4. There are 244 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 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.1015-10dupT		intron	N/A	NP_001351834.1
	LRBA	NM_001440430.1		c.1015-10dupT		intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.1015-10dupT		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.1015-10_1015-9insT		intron	N/A	ENSP00000498582.2
	LRBA	ENST00000357115.9	TSL:1	c.1015-10_1015-9insT		intron	N/A	ENSP00000349629.3
	LRBA	ENST00000510413.5	TSL:1	c.1015-10_1015-9insT		intron	N/A	ENSP00000421552.1

Frequencies

GnomAD3 genomes AF: 0.00497 AC: 495 AN: 99588 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00666

Gnomad ASJ AF: 0.00495

Gnomad EAS AF: 0.000279

Gnomad SAS AF: 0.00218

Gnomad FIN AF: 0.00617

Gnomad MID AF: 0.00472

Gnomad NFE AF: 0.00480

Gnomad OTH AF: 0.00436

GnomAD2 exomes AF: 0.0445 AC: 2734 AN: 61426 AF XY: 0.0445

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.0589

Gnomad ASJ exome AF: 0.0681

Gnomad EAS exome AF: 0.0398

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0420

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0351 AC: 28846 AN: 821804 Hom.: 7 Cov.: 20 AF XY: 0.0346 AC XY: 13832 AN XY: 400182

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0352 AC: 650 AN: 18474

American (AMR) AF: 0.0337 AC: 542 AN: 16060

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 429 AN: 12296

East Asian (EAS) AF: 0.0244 AC: 535 AN: 21960

South Asian (SAS) AF: 0.0424 AC: 1422 AN: 33530

European-Finnish (FIN) AF: 0.0243 AC: 715 AN: 29422

Middle Eastern (MID) AF: 0.0224 AC: 77 AN: 3432

European-Non Finnish (NFE) AF: 0.0359 AC: 23454 AN: 654122

Other (OTH) AF: 0.0314 AC: 1022 AN: 32508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00497 AC: 495 AN: 99596 Hom.: 0 Cov.: 32 AF XY: 0.00503 AC XY: 244 AN XY: 48508

African (AFR) AF: 0.00542 AC: 150 AN: 27684

American (AMR) AF: 0.00666 AC: 68 AN: 10214

Ashkenazi Jewish (ASJ) AF: 0.00495 AC: 11 AN: 2220

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3574

South Asian (SAS) AF: 0.00219 AC: 7 AN: 3196

European-Finnish (FIN) AF: 0.00617 AC: 38 AN: 6160

Middle Eastern (MID) AF: 0.00515 AC: 1 AN: 194

European-Non Finnish (NFE) AF: 0.00480 AC: 213 AN: 44344

Other (OTH) AF: 0.00433 AC: 6 AN: 1386

Alfa AF: 0.000507 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.26
Mutation Taster		=100/0	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: rs753223643; hg19: chr4-151835502;