chr4-150761851-TA-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_001364905.1(LRBA):​c.5581-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,221,092 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.018 (0 hom.)
• Consequence: LRBA NM_001364905.1 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Variant has high frequency in the SAS (0.0252) population. However there is too low homozygotes in high coverage region: (expected more than 76, got 0).
• BP6: Variant 4-150761851-TA-T is Benign according to our data. Variant chr4-150761851-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1165253.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRBA	NM_001364905.1	c.5581-5delT		splice_region_variant, intron_variant	Intron 34 of 56	ENST00000651943.2	NP_001351834.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRBA	ENST00000651943.2	c.5581-5delT		splice_region_variant, intron_variant	Intron 34 of 56		NM_001364905.1	ENSP00000498582.2

Frequencies

GnomAD3 genomes AF: 0.000359 AC: 52 AN: 144988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000202

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00269

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.000168

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0166 AC: 2017 AN: 121568 AF XY: 0.0160

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.0273

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0270

Gnomad FIN exome AF: 0.00511

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0179 AC: 19309 AN: 1076028 Hom.: 0 Cov.: 20 AF XY: 0.0179 AC XY: 9491 AN XY: 531480

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

African (AFR) AF: 0.0190 AC: 422 AN: 22204

American (AMR) AF: 0.0206 AC: 428 AN: 20788

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 300 AN: 16276

East Asian (EAS) AF: 0.0151 AC: 394 AN: 26048

South Asian (SAS) AF: 0.0264 AC: 1383 AN: 52454

European-Finnish (FIN) AF: 0.00865 AC: 350 AN: 40484

Middle Eastern (MID) AF: 0.0107 AC: 47 AN: 4390

European-Non Finnish (NFE) AF: 0.0178 AC: 15176 AN: 850644

Other (OTH) AF: 0.0189 AC: 809 AN: 42740

⚠️ 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: 0.000358 AC: 52 AN: 145064 Hom.: 0 Cov.: 32 AF XY: 0.000326 AC XY: 23 AN XY: 70454

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

African (AFR) AF: 0.000201 AC: 8 AN: 39788

American (AMR) AF: 0.000347 AC: 5 AN: 14426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3368

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

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4552

European-Finnish (FIN) AF: 0.00269 AC: 25 AN: 9298

Middle Eastern (MID) AF: 0.00355 AC: 1 AN: 282

European-Non Finnish (NFE) AF: 0.000168 AC: 11 AN: 65438

Other (OTH) AF: 0.00 AC: 0 AN: 1986

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0245 Hom.: 2

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Combined immunodeficiency due to LRBA deficiency Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=82/18	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: rs760075270; hg19: chr4-151683003; COSMIC: COSV63955363;