rs3829462

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000236.3(LIPC):c.1068C>A(p.Phe356Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.971 in 1,222,610 control chromosomes in the GnomAD database, including 576,991 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.95 ( 68390 hom., cov: 32)

Exomes 𝑓: 0.97 ( 508601 hom. )

Consequence

LIPC
NM_000236.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

LIPC (HGNC:6619): (lipase C, hepatic type) Enables phospholipase A1 activity and triglyceride lipase activity. Involved in several processes, including lipid homeostasis; plasma lipoprotein particle remodeling; and triglyceride catabolic process. Located in extracellular space. Implicated in several diseases, including Alzheimer's disease; coronary artery disease; familial combined hyperlipidemia; peripheral vascular disease; and type 2 diabetes mellitus. Biomarker of hyperinsulinism; obesity; and type 1 diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

LIPC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5836674E-6).

BP6

Variant 15-58560880-C-A is Benign according to our data. Variant chr15-58560880-C-A is described in ClinVar as [Benign]. Clinvar id is 316673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-58560880-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPC	NM_000236.3 linkuse as main transcript	c.1068C>A	p.Phe356Leu	missense_variant	7/9	ENST00000299022.10	NP_000227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPC	ENST00000299022.10 linkuse as main transcript	c.1068C>A	p.Phe356Leu	missense_variant	7/9	1	NM_000236.3	ENSP00000299022	P1

Frequencies

GnomAD3 genomes

AF:

0.946

AC:

143983

AN:

152158

Hom.:

68356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.858

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.982

Gnomad ASJ

AF:

0.998

Gnomad EAS

AF:

0.936

Gnomad SAS

AF:

0.986

Gnomad FIN

AF:

0.946

Gnomad MID

AF:

0.987

Gnomad NFE

AF:

0.986

Gnomad OTH

AF:

0.967

GnomAD3 exomes

AF:

0.972

AC:

244028

AN:

251044

Hom.:

118756

AF XY:

0.975

AC XY:

132316

AN XY:

135712

show subpopulations

Gnomad AFR exome

AF:

0.861

Gnomad AMR exome

AF:

0.991

Gnomad ASJ exome

AF:

0.997

Gnomad EAS exome

AF:

0.942

Gnomad SAS exome

AF:

0.988

Gnomad FIN exome

AF:

0.949

Gnomad NFE exome

AF:

0.985

Gnomad OTH exome

AF:

0.981

GnomAD4 exome

AF:

0.974

AC:

1042863

AN:

1070334

Hom.:

508601

Cov.:

AF XY:

0.976

AC XY:

537307

AN XY:

550598

show subpopulations

Gnomad4 AFR exome

AF:

0.842

Gnomad4 AMR exome

AF:

0.989

Gnomad4 ASJ exome

AF:

0.998

Gnomad4 EAS exome

AF:

0.908

Gnomad4 SAS exome

AF:

0.986

Gnomad4 FIN exome

AF:

0.948

Gnomad4 NFE exome

AF:

0.981

Gnomad4 OTH exome

AF:

0.972

GnomAD4 genome

AF:

0.946

AC:

144068

AN:

152276

Hom.:

68390

Cov.:

AF XY:

0.946

AC XY:

70435

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.858

Gnomad4 AMR

AF:

0.982

Gnomad4 ASJ

AF:

0.998

Gnomad4 EAS

AF:

0.936

Gnomad4 SAS

AF:

0.986

Gnomad4 FIN

AF:

0.946

Gnomad4 NFE

AF:

0.986

Gnomad4 OTH

AF:

0.967

Alfa

AF:

0.978

Hom.:

151754

Bravo

AF:

0.945

TwinsUK

AF:

0.984

AC:

3650

ALSPAC

AF:

0.985

AC:

3798

ESP6500AA

AF:

0.867

AC:

3801

ESP6500EA

AF:

0.985

AC:

8458

ExAC

AF:

0.969

AC:

117614

Asia WGS

AF:

0.962

AC:

3345

AN:

3478

EpiCase

AF:

0.987

EpiControl

AF:

0.987

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	This variant is associated with the following publications: (PMID: 27884173, 8732782, 20981092, 19428034) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Hyperlipidemia due to hepatic triglyceride lipase deficiency

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

T;.;T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.058

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.60

T;T;.;T

MetaRNN

Benign

0.0000016

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.2

L;.;L;.

MutationTaster

Benign

3.5e-7

P;P;P;P

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.49

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.13

B;.;B;B

Vest4

0.13

MutPred

0.50

Loss of methylation at K357 (P = 0.0317);Loss of methylation at K357 (P = 0.0317);Loss of methylation at K357 (P = 0.0317);.;

MPC

0.11

ClinPred

0.014

GERP RS

3.9

Varity_R

0.22

gMVP

0.58

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

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