NM_000237.3:c.1421C>G

Variant names:

Variant summary

Our verdict is The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BA1PVS1_ModerateBP6_Strong

The NM_000237.3(LPL):c.1421C>G (p.Ser474*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. This is a loss-of-function variant that does not trigger NMD. The variant allele was found at a cumulative frequency of 0.0968 (AC=156,015) in the gnomAD database across 1,611,322 control chromosomes, including 7,879 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.119. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

Frequency

Genomes: 𝑓 0.090 ( 610 hom., cov: 32)

Exomes 𝑓: 0.098 ( 7269 hom. )

Consequence

LPL
NM_000237.3 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.429

Publications

727 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Natera, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
hyperlipidemia, familial combined, LPL related
Inheritance: AD, SD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, PanelApp Australia, Natera

LPL links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000237.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -10 points.

PVS1

Non-NMD frameshift: disease mechanism, end-terminal — moderate (PVS1 downgraded to PM); Stop-gained (exon 9 of 10) at amino acid 474 of 475; NMD not predicted. Loss of function is a known disease mechanism, though the variant is in the terminal region of the CDS.

BP6

ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1192 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000237.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.1421C>G	p.Ser474*	stop_gained	Exon 9 of 10	NP_000228.1	P06858

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LPL	ENST00000650287.1	MANE Select	c.1421C>G	p.Ser474*	stop_gained	Exon 9 of 10	ENSP00000497642.1	P06858
LPL	ENST00000965928.1		c.1421C>G	p.Ser474*	stop_gained	Exon 11 of 12	ENSP00000635987.1	P06858
LPL	ENST00000965929.1		c.1418C>G	p.Ser473*	stop_gained	Exon 9 of 10	ENSP00000635988.1	A0ACI8VCL6

Frequencies

GnomAD3 genomes

AF:

0.0902

AC:

13720

AN:

152082

Hom.:

611

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0704

Gnomad AMI

AF:

0.155

Gnomad AMR

AF:

0.0785

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.0967

Gnomad FIN

AF:

0.0909

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.101

Gnomad OTH

AF:

0.0884

GnomAD2 exomes

AF:

0.0922

AC:

23148

AN:

251182

AF XY:

0.0938

show subpopulations

Gnomad AFR exome

AF:

0.0716

Gnomad AMR exome

AF:

0.0553

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.0882

Gnomad NFE exome

AF:

0.101

Gnomad OTH exome

AF:

0.0950

GnomAD4 exome

AF:

0.0975

AC:

142308

AN:

1459122

Hom.:

7269

Cov.:

AF XY:

0.0979

AC XY:

71091

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.0662

AC:

2214

AN:

33446

American (AMR)

AF:

0.0579

AC:

2589

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.106

AC:

2769

AN:

26102

East Asian (EAS)

AF:

0.122

AC:

4840

AN:

39656

South Asian (SAS)

AF:

0.0941

AC:

8106

AN:

86140

European-Finnish (FIN)

AF:

0.0888

AC:

4740

AN:

53352

Middle Eastern (MID)

AF:

0.0919

AC:

529

AN:

5754

European-Non Finnish (NFE)

AF:

0.100

AC:

111020

AN:

1109704

Other (OTH)

AF:

0.0913

AC:

5501

AN:

60266

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

5969

11938

17906

23875

29844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4088

8176

12264

16352

20440

<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:

0.0901

AC:

13707

AN:

152200

Hom.:

610

Cov.:

AF XY:

0.0894

AC XY:

6652

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0702

AC:

2916

AN:

41546

American (AMR)

AF:

0.0785

AC:

1199

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

365

AN:

3468

East Asian (EAS)

AF:

0.109

AC:

563

AN:

5160

South Asian (SAS)

AF:

0.0963

AC:

464

AN:

4816

European-Finnish (FIN)

AF:

0.0909

AC:

964

AN:

10604

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.101

AC:

6881

AN:

68006

Other (OTH)

AF:

0.0875

AC:

185

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

639

1278

1917

2556

3195

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

TOPMed (Bravo)

AF:

0.0879

AC:

23273

AN:

264690

Hom.:

1103

ALFA (dbGaP/dbSNP Allele Frequency Aggregator)

AF:

0.0990

AC:

12022

AN:

121420

Hom.:

621

Local populations

ABraOM SABE-WGS-1171

AF:

0.0944

AC:

221

AN:

2342

Hom.:

ChinaMAP Phase 1

AF:

0.0912

Denmark Genome

AF:

0.120

AC:

AN:

300

ESP6500 (Exome Variant Server)

AF:

0.0863

AC:

1123

AN:

13006

show subpopulations

European American

AF:

0.0967

AC:

832

AN:

8600

African American

AF:

0.0660

AC:

291

AN:

4406

GenomeAsia100K

AF:

0.100

AC:

346

AN:

3478

show subpopulations

Oceania

AF:

0.0608

AC:

AN:

148

Hom.:

North-East Asia

AF:

0.105

AC:

AN:

702

Hom.:

South-East Asia

AF:

0.0751

AC:

AN:

692

Hom.:

South Asia

AF:

0.128

AC:

185

AN:

1448

Hom.:

Africa

AF:

0.0144

AC:

AN:

208

Hom.:

America

AF:

0.0192

AC:

AN:

Hom.:

West Eurasia

AF:

0.0965

AC:

AN:

228

Hom.:

Korea4K (4,157 Koreans)

AF:

0.116

AC:

840

AN:

7234

Qatari Genome

AF:

0.0825

AC:

165

AN:

2000

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.131

AC:

16028

AN:

122780

Hom.:

1040

Turkish Variome

AF:

0.104

AC:

698

AN:

6708

Hom.:

UK10K

AF:

0.107

AC:

811

AN:

7562

show subpopulations

TwinsUK

AF:

0.108

AC:

385

AN:

3574

ALSPAC

AF:

0.107

AC:

411

AN:

3854

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.102

AC:

917

AN:

8960

Hom.:

Case/control cohorts

Cohort

Cases

Controls

ASC

(Autism)

1070 / 11108AF: 0.0963270

1768 / 17610AF: 0.100398

BipEx

(Bipolar disorder (including schizoaffective))

2773 / 28420AF: 0.0975721

2802 / 28844AF: 0.0971433

Epi25

(Epilepsy)

4233 / 41946AF: 0.100915

6170 / 66536AF: 0.0927318

SCHEMA

(Schizophrenia)

13524 / 128696AF: 0.105085

21829 / 203540AF: 0.107247

Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Hyperlipoproteinemia, type I (2)

Cardiovascular phenotype (1)

Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I (1)

LPL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Benign

0.70

PhyloP100

0.43

AlphaGenome AVI

Pathogenic

(source)

GPN-Star LLR

-9.4

(source)

GPN-Star score

9.4

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.20

Position offset: -3

Pangolin (max)

Uncertain

0.23

(source)

Pangolin loss

0.23

Position offset: 6

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

Case/control cohorts

ClinVar

Computational scores

Splicing

Publications

Other links and lift over