4-150588056-C-T

Variant names:

• chr4-150588056-C-T
• rs142598024
• NM_001364905.1:c.6322G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001364905.1(LRBA):​c.6322G>A​(p.Asp2108Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000275 in 1,611,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D2108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 5.05
• Publications: 2 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022561938).
• BP6: Variant 4-150588056-C-T is Benign according to our data. Variant chr4-150588056-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197442.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000271 (396/1459518) while in subpopulation AMR AF = 0.00218 (97/44438). AF 95% confidence interval is 0.00183. There are 0 homozygotes in GnomAdExome4. There are 182 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.6322G>A	p.Asp2108Asn	missense	Exon 40 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.6355G>A	p.Asp2119Asn	missense	Exon 41 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.6355G>A	p.Asp2119Asn	missense	Exon 41 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.6322G>A	p.Asp2108Asn	missense	Exon 40 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.6355G>A	p.Asp2119Asn	missense	Exon 41 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.6322G>A	p.Asp2108Asn	missense	Exon 40 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.000316 AC: 48 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000449 AC: 112 AN: 249394 AF XY: 0.000445

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00229

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.000826

GnomAD4 exome AF: 0.000271 AC: 396 AN: 1459518 Hom.: 0 Cov.: 31 AF XY: 0.000251 AC XY: 182 AN XY: 725936

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00218 AC: 97 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000351 AC: 3 AN: 85502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.000253 AC: 281 AN: 1110960

Other (OTH) AF: 0.000249 AC: 15 AN: 60338

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74358

African (AFR) AF: 0.000145 AC: 6 AN: 41504

American (AMR) AF: 0.00164 AC: 25 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68008

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.000548

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000387 AC: 47

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000238

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.42
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.1
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Benign	0.24
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.050	T
Polyphen		0.23	B
Vest4		0.42
MVP		0.55
MPC		0.53
ClinPred		0.13	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.59
gMVP		0.57
Mutation Taster		=61/39	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: rs142598024; hg19: chr4-151509208; COSMIC: COSV58263016; COSMIC: COSV58263016;