chr4-150908428-T-C

Variant names:

• chr4-150908428-T-C
• rs116355217
• NM_001364905.1:c.1399A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001364905.1(LRBA):​c.1399A>G​(p.Met467Val) variant causes a missense change. The variant allele was found at a frequency of 0.00329 in 1,608,406 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (8 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• Conservation: PhyloP100: 4.28
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015882492).
• BP6: Variant 4-150908428-T-C is Benign according to our data. Variant chr4-150908428-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287150.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (321/152306) while in subpopulation NFE AF = 0.00363 (247/68014). AF 95% confidence interval is 0.00326. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.1399A>G	p.Met467Val	missense	Exon 11 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.1399A>G	p.Met467Val	missense	Exon 11 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.1399A>G	p.Met467Val	missense	Exon 11 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.1399A>G	p.Met467Val	missense	Exon 11 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.1399A>G	p.Met467Val	missense	Exon 11 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.1399A>G	p.Met467Val	missense	Exon 11 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 321 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00363

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00212 AC: 521 AN: 245372 AF XY: 0.00219

Gnomad AFR exome AF: 0.000867

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00144

Gnomad NFE exome AF: 0.00398

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00341 AC: 4963 AN: 1456100 Hom.: 8 Cov.: 30 AF XY: 0.00329 AC XY: 2385 AN XY: 723922

African (AFR) AF: 0.000392 AC: 13 AN: 33158

American (AMR) AF: 0.000512 AC: 22 AN: 42994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84252

European-Finnish (FIN) AF: 0.00141 AC: 75 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00422 AC: 4692 AN: 1110718

Other (OTH) AF: 0.00266 AC: 160 AN: 60226

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74478

African (AFR) AF: 0.000721 AC: 30 AN: 41582

American (AMR) AF: 0.000851 AC: 13 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00363 AC: 247 AN: 68014

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

Alfa AF: 0.00303 Hom.: 2

Bravo AF: 0.00203

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.00215 AC: 261

EpiCase AF: 0.00344

EpiControl AF: 0.00326

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Combined immunodeficiency due to LRBA deficiency (5)
-	2	1	not provided (3)
-	1	2	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.042
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.3
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.0070	B
Vest4		0.78
MVP		0.41
MPC		0.12
ClinPred		0.029	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.42
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs116355217; hg19: chr4-151829580;