Genetic Variant LBP:p.Pro333Leu (chr20-38369011-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004139.5(LBP):c.998C>T(p.Pro333Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0763 in 1,613,568 control chromosomes in the GnomAD database, including 5,325 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.079 ( 561 hom., cov: 32)

Exomes 𝑓: 0.076 ( 4764 hom. )

Consequence

LBP
NM_004139.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.61

Publications

34 publications found

Variant links:

Genes affected

LBP (HGNC:6517): (lipopolysaccharide binding protein) The protein encoded by this gene is involved in the acute-phase immunologic response to gram-negative bacterial infections. Gram-negative bacteria contain a glycolipid, lipopolysaccharide (LPS), on their outer cell wall. Together with bactericidal permeability-increasing protein (BPI), the encoded protein binds LPS and interacts with the CD14 receptor, probably playing a role in regulating LPS-dependent monocyte responses. Studies in mice suggest that the encoded protein is necessary for the rapid acute-phase response to LPS but not for the clearance of LPS from circulation. This protein is part of a family of structurally and functionally related proteins, including BPI, plasma cholesteryl ester transfer protein (CETP), and phospholipid transfer protein (PLTP). [provided by RefSeq, Apr 2012]

LBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028777719).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LBP	NM_004139.5 link	c.998C>T	p.Pro333Leu	missense_variant	Exon 10 of 15	ENST00000217407.3	NP_004130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LBP	ENST00000217407.3 link	c.998C>T	p.Pro333Leu	missense_variant	Exon 10 of 15	1	NM_004139.5	ENSP00000217407.2

Frequencies

GnomAD3 genomes

AF:

0.0793

AC:

12055

AN:

152068

Hom.:

560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0901

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.0550

Gnomad ASJ

AF:

0.0305

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0473

Gnomad FIN

AF:

0.143

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0803

Gnomad OTH

AF:

0.0606

GnomAD2 exomes

AF:

0.0657

AC:

16517

AN:

251406

AF XY:

0.0654

show subpopulations

Gnomad AFR exome

AF:

0.0916

Gnomad AMR exome

AF:

0.0319

Gnomad ASJ exome

AF:

0.0309

Gnomad EAS exome

AF:

0.000707

Gnomad FIN exome

AF:

0.140

Gnomad NFE exome

AF:

0.0759

Gnomad OTH exome

AF:

0.0688

GnomAD4 exome

AF:

0.0760

AC:

111036

AN:

1461382

Hom.:

4764

Cov.:

AF XY:

0.0750

AC XY:

54517

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0912

AC:

3051

AN:

33464

American (AMR)

AF:

0.0333

AC:

1491

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0338

AC:

884

AN:

26132

East Asian (EAS)

AF:

0.000327

AC:

AN:

39698

South Asian (SAS)

AF:

0.0491

AC:

4238

AN:

86254

European-Finnish (FIN)

AF:

0.139

AC:

7401

AN:

53406

Middle Eastern (MID)

AF:

0.0192

AC:

111

AN:

5768

European-Non Finnish (NFE)

AF:

0.0804

AC:

89406

AN:

1111554

Other (OTH)

AF:

0.0735

AC:

4441

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

5338

10676

16014

21352

26690

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3284

6568

9852

13136

16420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0793

AC:

12069

AN:

152186

Hom.:

561

Cov.:

AF XY:

0.0801

AC XY:

5958

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.0901

AC:

3743

AN:

41534

American (AMR)

AF:

0.0549

AC:

838

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0305

AC:

106

AN:

3470

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.0482

AC:

232

AN:

4814

European-Finnish (FIN)

AF:

0.143

AC:

1517

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0803

AC:

5462

AN:

68012

Other (OTH)

AF:

0.0600

AC:

127

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

557

1115

1672

2230

2787

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

134

268

402

536

670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0733

Hom.:

1818

Bravo

AF:

0.0715

TwinsUK

AF:

0.0860

AC:

319

ALSPAC

AF:

0.0820

AC:

316

ESP6500AA

AF:

0.0960

AC:

423

ESP6500EA

AF:

0.0801

AC:

689

ExAC

AF:

0.0653

AC:

7923

Asia WGS

AF:

0.0300

AC:

105

AN:

3478

EpiCase

AF:

0.0737

EpiControl

AF:

0.0657

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 17, 2013

OMIM

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.34

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0029

MetaSVM

Benign

-0.97

MutationAssessor

Pathogenic

3.2

PhyloP100

4.6

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-9.5

REVEL

Benign

0.26

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.30

MPC

0.49

ClinPred

0.063

GERP RS

4.6

Varity_R

0.92

gMVP

0.65

Mutation Taster

=82/18

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over