rs121912502

Positions:

chr15-58548387-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_000236.3(LIPC):c.866C>T(p.Ser289Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,162 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S289S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00071 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

LIPC
NM_000236.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:1

Conservation

PhyloP100: 7.84

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 Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LIPC	NM_000236.3 linkuse as main transcript	c.866C>T	p.Ser289Phe	missense_variant	6/9	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.866C>T	p.Ser289Phe	missense_variant	6/9	1	NM_000236.3	ENSP00000299022.5		P11150

Frequencies

GnomAD3 genomes

AF:

0.000710

AC:

108

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00101

AC:

255

AN:

251294

Hom.:

AF XY:

0.000994

AC XY:

135

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00119

AC:

1746

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

875

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000824

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.000709

AC:

108

AN:

152324

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00126

Hom.:

Bravo

AF:

0.000570

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00119

AC:

144

EpiCase

AF:

0.000763

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperlipidemia due to hepatic triglyceride lipase deficiency

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 16, 2014	The p.Ser289Phe variant in LIPC has been reported in 1 compound heterozygous individual with hepatic lipase deficiency and segregated with disease in 3 affected compound heterozygous relatives from 1 family (Hegele 1991). This variant has been identified in 0.13% (11/8584) of European American chromosomes and 0.05% (4/4384) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs121912502). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro assays indicate the p.Ser289Phe variant leads to reduced LIPC activity (Durstenfeld 1994). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analysis also suggest that the p.Ser289Phe variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ser289Phe variant is uncertain. -
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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 30, 1991	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2024	PP3, PP4, PM1_supporting, PS3_supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.80

D;.;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.84

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;.;H;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.6

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;D;D

Vest4

1.0

MVP

0.98

MPC

0.44

ClinPred

0.75

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.99

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