rs113298164

Positions:

chr15-58563549-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000236.3(LIPC):c.1214C>T(p.Thr405Met) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,614,152 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0028 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 17 hom. )

Consequence

LIPC
NM_000236.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5B:3

Conservation

PhyloP100: 7.18

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:

LIPC (HGNC:):

LIPC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015030295).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPC	NM_000236.3 linkuse as main transcript	c.1214C>T	p.Thr405Met	missense_variant	8/9	ENST00000299022.10	NP_000227.2	P11150A6H8L5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPC	ENST00000299022.10 linkuse as main transcript	c.1214C>T	p.Thr405Met	missense_variant	8/9	1	NM_000236.3	ENSP00000299022.5		P11150

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

432

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0146

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00360

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00293

AC:

737

AN:

251448

Hom.:

AF XY:

0.00274

AC XY:

372

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000665

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0157

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00252

AC:

3682

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00247

AC XY:

1794

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.000648

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0163

Gnomad4 NFE exome

AF:

0.00236

Gnomad4 OTH exome

AF:

0.00228

GnomAD4 genome

AF:

0.00284

AC:

432

AN:

152292

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000851

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0146

Gnomad4 NFE

AF:

0.00360

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00266

Hom.:

Bravo

AF:

0.00148

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00276

AC:

335

EpiCase

AF:

0.00240

EpiControl

AF:

0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	This variant is associated with the following publications: (PMID: 32041611, 31589614, 31980526, 30333156, 28870971, 1671786, 24082139, 24497850, 20981092, 8732782, 1883393, 23685560, 8123642) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	LIPC: BS1 -

Hyperlipidemia due to hepatic triglyceride lipase deficiency

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000236.2:c.1214C>T in the LIPC gene has an allele frequency of 0.015 in European(Finnish) subpopulation in the gnomAD database.Functional studies demonstrate that p.Thr405Met has reduced enzymatic activity (PMID: 1883393). It was detected in multiple individuals with autosomal recessive Hepatic lipase deficiency, compound heterozygous with c.1214C>T (p.Thr405Met) (PMID: 1883393).The patient's phenotype is highly specific for LIPC gene (PMID: 1671786). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3; PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Type 2 diabetes mellitus

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2020

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr405Met variant in LIPC (also reported as p.Thr383Met in the literature) has been identified in the compound heterozygous state in at least 2 individuals with hepatic lipase deficiency and segregated with disease in 5 affected relatives from 2 families (Hegele 1991 PMID: 1883393, Hegele 1991 PMID: 1671786, Ruel 2003 PMID: 12777476 ). This variant has also been identified in the heterozygous state in 3 individuals with biochemical features consistent with hepatic lipase deficiency (Knudsen 1996 PMID: 8732782, Motazacker 2013 PMID: 23685560, Geller 2018 PMID: 30333156). Additionally, this variant has been reported in ClinVar (Variation ID # 14451) and has been identified in 1.5% (388/25112) of Finnish chromosomes, including 3 homozygotes, and 0.3% (460/129166) of European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Knudsen 1996 PMID: 8732782, Durstenfeld 1994 PMID: 8123642); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain as it is unclear what clinical effect of the biochemical change in lipid levels has on people with hepatic lipase deficiency, particularly on how they affect the risk of atherosclerosis in some individuals and not in others and whether that risk is greater than individuals in the general population (Brunzell 2011 PMID: 21986251, Kobayashi 2015 PMID: 25995285). ACMG/AMP Criteria applied:PP1_Strong, PM3, PS3_Supporting. -

Type 1 diabetes mellitus 2;C2675071:High density lipoprotein cholesterol level quantitative trait locus 12;C3151466:Hyperlipidemia due to hepatic triglyceride lipase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;.;T;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

D;D;.;D

MetaRNN

Benign

0.015

T;T;T;T

MetaSVM

Uncertain

-0.0078

MutationAssessor

Pathogenic

3.1

M;.;M;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.043

D;T;D;T

Sift4G

Benign

0.16

T;T;T;T

Polyphen

1.0

D;.;D;D

Vest4

0.76

MVP

0.85

MPC

0.43

ClinPred

0.040

GERP RS

5.9

Varity_R

0.17

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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