4-150761851-TAAA-TAAAA

Variant names:

• chr4-150761851-T-TA
• rs760075270
• NM_001364905.1:c.5581-5dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM2 BP6_Very_Strong

The NM_001364905.1(LRBA):​c.5581-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0091 in 1,264,252 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (1 hom., cov: 32)
  • Exomes 𝑓: 0.010 (0 hom.)
• Consequence: LRBA NM_001364905.1 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.30
• 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0118) population. However there is too low homozygotes in high coverage region: (expected more than 26, got 1).
• BP6: Variant 4-150761851-T-TA is Benign according to our data. Variant chr4-150761851-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	NM_001364905.1	MANE Select	c.5581-5dupT		splice_region intron	N/A	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.5581-5dupT		splice_region intron	N/A	NP_001427359.1
	LRBA	NM_006726.5		c.5581-5dupT		splice_region intron	N/A	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.5581-5_5581-4insT		splice_region intron	N/A	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.5581-5_5581-4insT		splice_region intron	N/A	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.5581-5_5581-4insT		splice_region intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 82 AN: 145126 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000624

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000214

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000229

Gnomad OTH AF: 0.00203

GnomAD2 exomes AF: 0.00576 AC: 700 AN: 121568 AF XY: 0.00569

Gnomad AFR exome AF: 0.00807

Gnomad AMR exome AF: 0.0101

Gnomad ASJ exome AF: 0.00896

Gnomad EAS exome AF: 0.0118

Gnomad FIN exome AF: 0.00148

Gnomad NFE exome AF: 0.00446

Gnomad OTH exome AF: 0.0117

GnomAD4 exome AF: 0.0102 AC: 11428 AN: 1119050 Hom.: 0 Cov.: 20 AF XY: 0.00986 AC XY: 5467 AN XY: 554650

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

African (AFR) AF: 0.0103 AC: 239 AN: 23094

American (AMR) AF: 0.00889 AC: 196 AN: 22046

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 144 AN: 17816

East Asian (EAS) AF: 0.00655 AC: 183 AN: 27924

South Asian (SAS) AF: 0.0126 AC: 708 AN: 56186

European-Finnish (FIN) AF: 0.00366 AC: 156 AN: 42648

Middle Eastern (MID) AF: 0.00548 AC: 25 AN: 4566

European-Non Finnish (NFE) AF: 0.0106 AC: 9319 AN: 880164

Other (OTH) AF: 0.0103 AC: 458 AN: 44606

⚠️ 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: 0.000572 AC: 83 AN: 145202 Hom.: 1 Cov.: 32 AF XY: 0.000581 AC XY: 41 AN XY: 70530

African (AFR) AF: 0.00131 AC: 52 AN: 39800

American (AMR) AF: 0.000623 AC: 9 AN: 14436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3374

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5034

South Asian (SAS) AF: 0.00 AC: 0 AN: 4552

European-Finnish (FIN) AF: 0.000214 AC: 2 AN: 9346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.000229 AC: 15 AN: 65500

Other (OTH) AF: 0.00201 AC: 4 AN: 1986

Alfa AF: 0.00790 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Combined immunodeficiency due to LRBA deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=97/3	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs760075270;

hg19: chr4-151683003;