NM_000237.3:c.1421C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_000237.3(LPL):c.1421C>G(p.Ser474*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,611,322 control chromosomes in the GnomAD database, including 7,879 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S474S) has been classified as 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:10

Conservation

PhyloP100: 0.429

Publications

725 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: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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 -14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0049 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

BP6

Variant 8-19962213-C-G is Benign according to our data. Variant chr8-19962213-C-G is described in ClinVar as Benign. ClinVar VariationId is 1534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.1421C>G	p.Ser474*	stop_gained	Exon 9 of 10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	ENST00000650287.1 link	c.1421C>G	p.Ser474*	stop_gained	Exon 9 of 10	NM_000237.3	ENSP00000497642.1	P06858
LPL	ENST00000650478.1 link	n.*244C>G		non_coding_transcript_exon_variant	Exon 3 of 4		ENSP00000497560.1	A0A3B3IT60
LPL	ENST00000650478.1 link	n.*244C>G		3_prime_UTR_variant	Exon 3 of 4		ENSP00000497560.1	A0A3B3IT60

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

Alfa

AF:

0.0996

Hom.:

591

Bravo

AF:

0.0879

TwinsUK

AF:

0.108

AC:

400

ALSPAC

AF:

0.107

AC:

411

ESP6500AA

AF:

0.0660

AC:

291

ESP6500EA

AF:

0.0967

AC:

832

ExAC

AF:

0.0934

AC:

11341

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.111

EpiControl

AF:

0.107

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Sep 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 33339817, 8839720, 33111339, 15049943, 28267856, 23050023, 26999119, 26975783, 24974629, 24603370, 28640651, 29687697, 29632382, 29083407, 27516387, 29083408, 27984852, 27535653, 24704550, 26934567, 27055971, 28008009, 2216713, 17029199, 15793775, 21162862, 21816453, 25525159, 24039871, 19148283, 17560523, 19034041, 19664517, 19556723, 18187430, 19368142, 23113749, 25579610, 24176758, 19367320, 19018513, 17291198, 10450862, 17555736, 22244040, 18922999, 19185650) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: LPL c.1421C>G (p.Ser474X) results in a premature termination two codons before the normal termination codon. The variant allele was found at a frequency of 0.092 in 251182 control chromosomes in the gnomAD database, including 1212 homozygotes. The observed variant frequency is approximately 27-fold of the estimated maximal expected allele frequency for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency phenotype (0.0034), strongly suggesting that the variant is benign. Three ClinVar submitters have assessed this variant since 2014: all have classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Hyperlipoproteinemia, type I

Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 15, 1992

OMIM

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Benign:1

May 02, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 03, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

LPL-related disorder

Benign:1

Jun 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Vest4

0.58

GERP RS

4.0

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

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