dbSNP rs753223643: LRBA:c.1015-12_1015-10delTTT (chr4-150914350-GAAA-G) – 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.1015-12_1015-10delTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000976 in 921,816 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000098 ( 0 hom. )

Consequence

LRBA
NM_001364905.1 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.11

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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

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	UniProt
LRBA	NM_001364905.1	MANE Select	c.1015-12_1015-10delTTT	intron	N/A	NP_001351834.1	A0A494C1L5
LRBA	NM_001440430.1		c.1015-12_1015-10delTTT	intron	N/A	NP_001427359.1
LRBA	NM_006726.5		c.1015-12_1015-10delTTT	intron	N/A	NP_006717.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LRBA	ENST00000651943.2	MANE Select	c.1015-12_1015-10delTTT	intron	N/A	ENSP00000498582.2	A0A494C1L5
LRBA	ENST00000357115.9	TSL:1	c.1015-12_1015-10delTTT	intron	N/A	ENSP00000349629.3	P50851-1
LRBA	ENST00000510413.5	TSL:1	c.1015-12_1015-10delTTT	intron	N/A	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000976

AC:

AN:

921816

Hom.:

AF XY:

0.0000111

AC XY:

AN XY:

448974

show subpopulations

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

African (AFR)

AF:

0.0000487

AC:

AN:

20552

American (AMR)

AF:

0.00

AC:

AN:

17696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13964

East Asian (EAS)

AF:

0.0000402

AC:

AN:

24904

South Asian (SAS)

AF:

0.0000274

AC:

AN:

36454

European-Finnish (FIN)

AF:

0.0000308

AC:

AN:

32460

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3682

European-Non Finnish (NFE)

AF:

0.00000544

AC:

AN:

735606

Other (OTH)

AF:

0.0000274

AC:

AN:

36498

⚠️ 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: 0.231

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.1

Mutation Taster

=100/0

polymorphism

(source)

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

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over