rs62346982

Variant names:

• chr4-150321257-T-G
• rs62346982
• NM_001364905.1:c.7564A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-150321257-T-G
• chr4-150321257-T-C

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.7564A>C​(p.Thr2522Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00698 in 1,612,060 control chromosomes in the GnomAD database, including 52 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).

• Frequency:
  • Genomes: 𝑓 0.0045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0072 (52 hom.)
• Consequence: LRBA NM_001364905.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.458
• Publications: 8 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=0.008562565).
• BP6: Variant 4-150321257-T-G is Benign according to our data. Variant chr4-150321257-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 439869.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00446 (679/152124) while in subpopulation NFE AF = 0.00799 (543/67990). AF 95% confidence interval is 0.00743. There are 0 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 52 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.7564A>C	p.Thr2522Pro	missense	Exon 50 of 57	NP_001351834.1	A0A494C1L5
	LRBA	NM_001440430.1		c.7612A>C	p.Thr2538Pro	missense	Exon 51 of 58	NP_001427359.1
	LRBA	NM_006726.5		c.7597A>C	p.Thr2533Pro	missense	Exon 51 of 58	NP_006717.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRBA	ENST00000651943.2	MANE Select	c.7564A>C	p.Thr2522Pro	missense	Exon 50 of 57	ENSP00000498582.2	A0A494C1L5
	LRBA	ENST00000357115.9	TSL:1	c.7597A>C	p.Thr2533Pro	missense	Exon 51 of 58	ENSP00000349629.3	P50851-1
	LRBA	ENST00000510413.5	TSL:1	c.7564A>C	p.Thr2522Pro	missense	Exon 50 of 57	ENSP00000421552.1	P50851-2

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 679 AN: 152006 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00799

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00424 AC: 1051 AN: 248108 AF XY: 0.00408

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.000688

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00817

Gnomad OTH exome AF: 0.00430

GnomAD4 exome AF: 0.00725 AC: 10581 AN: 1459936 Hom.: 52 Cov.: 31 AF XY: 0.00701 AC XY: 5092 AN XY: 726282

African (AFR) AF: 0.00135 AC: 45 AN: 33364

American (AMR) AF: 0.000815 AC: 36 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.000151 AC: 13 AN: 85838

European-Finnish (FIN) AF: 0.00227 AC: 121 AN: 53404

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5754

European-Non Finnish (NFE) AF: 0.00906 AC: 10065 AN: 1111408

Other (OTH) AF: 0.00416 AC: 251 AN: 60294

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74374

African (AFR) AF: 0.00164 AC: 68 AN: 41502

American (AMR) AF: 0.00223 AC: 34 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10586

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

European-Non Finnish (NFE) AF: 0.00799 AC: 543 AN: 67990

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00661 Hom.: 4

Bravo AF: 0.00487

TwinsUK AF: 0.00728 AC: 27

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00463 AC: 562

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00721

EpiControl AF: 0.00689

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.46
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.22	T
Polyphen		0.13	B
Vest4		0.43
MVP		0.44
MPC		0.18
ClinPred		0.0060	T
GERP RS		2.3
Varity_R		0.32
gMVP		0.28
Mutation Taster		=99/1	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: rs62346982; hg19: chr4-151242409;