NM_001364905.1:c.3743A>G

Variant names:

• chr4-150851967-T-C
• rs140860135
• NM_001364905.1:c.3743A>G

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.3743A>G​(p.Asn1248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000147 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. N1248D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00056 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 1.34
• 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

ENSG00000298996 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052304864).
• BP6: Variant 4-150851967-T-C is Benign according to our data. Variant chr4-150851967-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540379.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000565 (86/152308) while in subpopulation AFR AF = 0.00178 (74/41572). AF 95% confidence interval is 0.00145. There are 1 homozygotes in GnomAd4. There are 45 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.3743A>G	p.Asn1248Ser	missense	Exon 23 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.3743A>G	p.Asn1248Ser	missense	Exon 23 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.3743A>G	p.Asn1248Ser	missense	Exon 23 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.3743A>G	p.Asn1248Ser	missense	Exon 23 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.3743A>G	p.Asn1248Ser	missense	Exon 23 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.3743A>G	p.Asn1248Ser	missense	Exon 23 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251282 AF XY: 0.000228

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.000109 AC XY: 79 AN XY: 727216

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.000492 AC: 22 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39694

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000405 AC: 45 AN: 1111972

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152308 Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74482

African (AFR) AF: 0.00178 AC: 74 AN: 41572

American (AMR) AF: 0.000458 AC: 7 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5180

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.000665

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

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)
-	-	1	LRBA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.35
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.5	N
PhyloP100		1.3
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.99	N
REVEL	Benign	0.050
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.054
MVP		0.22
MPC		0.090
ClinPred		0.0038	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.017
gMVP		0.17
Mutation Taster		=95/5	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: rs140860135; hg19: chr4-151773119;