rs5934

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000237.3(LPL):c.1279G>A(p.Ala427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,058 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 24 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.269

Publications

18 publications found

Variant links:

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL Gene-Disease associations (from GenCC):

familial lipoprotein lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics
hyperlipidemia, familial combined, LPL related
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

LPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.

BP4

Computational evidence support a benign effect (MetaRNN=0.005454719).

BP6

Variant 8-19961040-G-A is Benign according to our data. Variant chr8-19961040-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00889 (1354/152240) while in subpopulation AFR AF = 0.0295 (1226/41542). AF 95% confidence interval is 0.0281. There are 16 homozygotes in GnomAd4. There are 645 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000237.3. 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
	LPL	NM_000237.3	MANE Select	c.1279G>A	p.Ala427Thr	missense	Exon 8 of 10	NP_000228.1	P06858

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPL	ENST00000650287.1	MANE Select	c.1279G>A	p.Ala427Thr	missense	Exon 8 of 10	ENSP00000497642.1	P06858
LPL	ENST00000965928.1		c.1279G>A	p.Ala427Thr	missense	Exon 10 of 12	ENSP00000635987.1
LPL	ENST00000965929.1		c.1276G>A	p.Ala426Thr	missense	Exon 8 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes

AF:

0.00891

AC:

1355

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00527

GnomAD2 exomes

AF:

0.00313

AC:

787

AN:

251196

AF XY:

0.00269

show subpopulations

Gnomad AFR exome

AF:

0.0298

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00138

AC:

2015

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

949

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0300

AC:

1005

AN:

33480

American (AMR)

AF:

0.00215

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0188

AC:

492

AN:

26132

East Asian (EAS)

AF:

0.000479

AC:

AN:

39692

South Asian (SAS)

AF:

0.000336

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000163

AC:

181

AN:

1111984

Other (OTH)

AF:

0.00296

AC:

179

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

101

201

302

402

503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.00889

AC:

1354

AN:

152240

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

645

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.0295

AC:

1226

AN:

41542

American (AMR)

AF:

0.00321

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0141

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000220

AC:

AN:

68028

Other (OTH)

AF:

0.00521

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

121

181

242

302

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00418

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00326

AC:

396

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hyperlipoproteinemia, type I (2)

not specified (2)

Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.4

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.076

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.71

PhyloP100

-0.27

PrimateAI

Benign

0.24

PROVEAN

Benign

0.39

REVEL

Benign

0.13

Sift

Benign

0.60

Sift4G

Benign

0.65

Polyphen

0.0

Vest4

0.10

MVP

0.62

MPC

0.075

ClinPred

0.00013

GERP RS

-0.38

Varity_R

0.058

gMVP

0.50

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over