rs113298164

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PS3BP4_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). ClinVar reports functional evidence for this variant: "SCV001142450: Functional studies demonstrate that p.Thr405Met has reduced enzymatic activity (PMID:1883393).". Synonymous variant affecting the same amino acid position (i.e. T405T) has been classified as Uncertain significance.

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:6B:3

Conservation

PhyloP100: 7.18

Publications

36 publications found

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 Gene-Disease associations (from GenCC):

hyperlipidemia due to hepatic triglyceride lipase deficiency
Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

LIPC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001142450: Functional studies demonstrate that p.Thr405Met has reduced enzymatic activity (PMID: 1883393).

BP4

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

BS2

High Homozygotes in GnomAd4 at 2 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPC	NM_000236.3	MANE Select	c.1214C>T	p.Thr405Met	missense	Exon 8 of 9	NP_000227.2	P11150

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LIPC	ENST00000299022.10	TSL:1 MANE Select	c.1214C>T	p.Thr405Met	missense	Exon 8 of 9	ENSP00000299022.5	P11150
LIPC	ENST00000414170.7	TSL:1	c.1214C>T	p.Thr405Met	missense	Exon 9 of 10	ENSP00000395569.3	E7EUJ1
LIPC	ENST00000559845.5	TSL:1	n.1071C>T		non_coding_transcript_exon	Exon 7 of 7

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

GnomAD2 exomes

AF:

0.00293

AC:

737

AN:

251448

AF XY:

0.00274

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 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

African (AFR)

AF:

0.000329

AC:

AN:

33480

American (AMR)

AF:

0.000648

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0163

AC:

868

AN:

53412

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00236

AC:

2626

AN:

1111986

Other (OTH)

AF:

0.00228

AC:

138

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

215

430

644

859

1074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.00284

AC:

432

AN:

152292

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

232

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41558

American (AMR)

AF:

0.000851

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0146

AC:

155

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00360

AC:

245

AN:

68026

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

109

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00263

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hyperlipidemia due to hepatic triglyceride lipase deficiency (3)

not specified (1)

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

Type 2 diabetes mellitus (1)

Type 2 diabetes mellitus;C3151466:Hyperlipidemia due to hepatic triglyceride lipase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.019

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.015

MetaSVM

Uncertain

-0.0078

MutationAssessor

Pathogenic

3.1

PhyloP100

7.2

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.45

Sift

Benign

0.043

Sift4G

Benign

0.16

Polyphen

1.0

Vest4

0.76

MVP

0.85

MPC

0.43

ClinPred

0.040

GERP RS

5.9

Varity_R

0.17

gMVP

0.68

Mutation Taster

=52/48

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over