Genetic Variant NM_001364905.1:c.5581-7_5581-5delTTT (chr4-150761851-TAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001364905.1(LRBA):c.5581-7_5581-5delTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000861 in 1,160,892 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

LRBA
NM_001364905.1 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.40

Publications

0 publications found

Variant links:

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

LRBA links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LRBA	NM_001364905.1	MANE Select	c.5581-7_5581-5delTTT	splice_region intron	N/A	NP_001351834.1
LRBA	NM_001440430.1		c.5581-7_5581-5delTTT	splice_region intron	N/A	NP_001427359.1
LRBA	NM_006726.5		c.5581-7_5581-5delTTT	splice_region intron	N/A	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
LRBA	ENST00000651943.2	MANE Select	c.5581-7_5581-5delTTT	splice_region intron	N/A	ENSP00000498582.2
LRBA	ENST00000357115.9	TSL:1	c.5581-7_5581-5delTTT	splice_region intron	N/A	ENSP00000349629.3
LRBA	ENST00000510413.5	TSL:1	c.5581-7_5581-5delTTT	splice_region intron	N/A	ENSP00000421552.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.61e-7

AC:

AN:

1160892

Hom.:

AF XY:

0.00

AC XY:

AN XY:

575662

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23954

American (AMR)

AF:

0.00

AC:

AN:

22710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18582

East Asian (EAS)

AF:

0.00

AC:

AN:

29126

South Asian (SAS)

AF:

0.00

AC:

AN:

58258

European-Finnish (FIN)

AF:

0.0000227

AC:

AN:

44020

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4686

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

913032

Other (OTH)

AF:

0.00

AC:

AN:

46524

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.4

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over