8-19962213-C-G

Position:

chr8-19962213-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The NM_000237.3(LPL):c.1421C>G(p.Ser474Ter) 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:8

Conservation

PhyloP100: 0.429

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19962213-C-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.1421C>G	p.Ser474Ter	stop_gained	9/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.1421C>G	p.Ser474Ter	stop_gained	9/10		NM_000237.3	P1
LPL	ENST00000650478.1 linkuse as main transcript	c.*244C>G		3_prime_UTR_variant, NMD_transcript_variant	3/4

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

GnomAD3 exomes

AF:

0.0922

AC:

23148

AN:

251182

Hom.:

1212

AF XY:

0.0938

AC XY:

12729

AN XY:

135736

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 SAS exome

AF:

0.0962

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

Gnomad4 AFR exome

AF:

0.0662

Gnomad4 AMR exome

AF:

0.0579

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.122

Gnomad4 SAS exome

AF:

0.0941

Gnomad4 FIN exome

AF:

0.0888

Gnomad4 NFE exome

AF:

0.100

Gnomad4 OTH exome

AF:

0.0913

GnomAD4 genome

AF:

0.0901

AC:

13707

AN:

152200

Hom.:

610

Cov.:

AF XY:

0.0894

AC XY:

6652

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0702

Gnomad4 AMR

AF:

0.0785

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.0963

Gnomad4 FIN

AF:

0.0909

Gnomad4 NFE

AF:

0.101

Gnomad4 OTH

AF:

0.0875

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	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) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Dec 16, 2021

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:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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. -

LIPOPROTEIN LIPASE POLYMORPHISM

Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Jan 15, 1992

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 02, 2022

- -

LPL-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 19, 2023

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

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Benign

0.70

MutationTaster

Benign

5.2e-7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over