rs35879351

Variant names:

• chr4-150599064-G-A
• rs35879351
• NM_001364905.1:c.5989C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-150599064-G-A
• chr4-150599064-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001364905.1(LRBA):​c.5989C>T​(p.Arg1997Cys) variant causes a missense change. The variant allele was found at a frequency of 0.027 in 1,613,952 control chromosomes in the GnomAD database, including 708 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1997S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.021 (51 hom., cov: 32)
  • Exomes 𝑓: 0.028 (657 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 6.22
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012158245).
• BP6: Variant 4-150599064-G-A is Benign according to our data. Variant chr4-150599064-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 403052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3202/152198) while in subpopulation NFE AF = 0.0313 (2127/68010). AF 95% confidence interval is 0.0302. There are 51 homozygotes in GnomAd4. There are 1558 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 AR gene

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.5989C>T	p.Arg1997Cys	missense	Exon 38 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.5989C>T	p.Arg1997Cys	missense	Exon 38 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.5989C>T	p.Arg1997Cys	missense	Exon 38 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.5989C>T	p.Arg1997Cys	missense	Exon 38 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.5989C>T	p.Arg1997Cys	missense	Exon 38 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.5989C>T	p.Arg1997Cys	missense	Exon 38 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3201 AN: 152080 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00995

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0313

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0239 AC: 6007 AN: 251238 AF XY: 0.0247

Gnomad AFR exome AF: 0.00418

Gnomad AMR exome AF: 0.0117

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0382

Gnomad NFE exome AF: 0.0353

Gnomad OTH exome AF: 0.0279

GnomAD4 exome AF: 0.0276 AC: 40351 AN: 1461754 Hom.: 657 Cov.: 31 AF XY: 0.0273 AC XY: 19829 AN XY: 727184

African (AFR) AF: 0.00427 AC: 143 AN: 33468

American (AMR) AF: 0.0129 AC: 575 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 575 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39692

South Asian (SAS) AF: 0.0114 AC: 984 AN: 86254

European-Finnish (FIN) AF: 0.0387 AC: 2069 AN: 53414

Middle Eastern (MID) AF: 0.0300 AC: 173 AN: 5768

European-Non Finnish (NFE) AF: 0.0308 AC: 34208 AN: 1111920

Other (OTH) AF: 0.0269 AC: 1623 AN: 60386

GnomAD4 genome AF: 0.0210 AC: 3202 AN: 152198 Hom.: 51 Cov.: 32 AF XY: 0.0209 AC XY: 1558 AN XY: 74412

African (AFR) AF: 0.00542 AC: 225 AN: 41542

American (AMR) AF: 0.0184 AC: 282 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3464

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5162

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.0360 AC: 381 AN: 10586

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0313 AC: 2127 AN: 68010

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0285 Hom.: 263

Bravo AF: 0.0199

TwinsUK AF: 0.0302 AC: 112

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.0323 AC: 278

ExAC AF: 0.0253 AC: 3070

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0311

EpiControl AF: 0.0313

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Combined immunodeficiency due to LRBA deficiency (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.61
MPC		0.61
ClinPred		0.020	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.47
gMVP		0.78
Mutation Taster		=93/7	polymorphism (auto)

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: rs35879351; hg19: chr4-151520216;