rs3829462

Positions:

• chr15-58560880-C-A
• chr15-58560880-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.54

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]

ACMG classification

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	UniProt
LIPC	NM_000236.3	c.1068C>A	p.Phe356Leu	missense_variant	7/9	ENST00000299022.10

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143983 AN: 152158 Hom.: 68356 Cov.: 32

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

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.: 15 AF XY: 0.976 AC XY: 537307 AN XY: 550598

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.: 32 AF XY: 0.946 AC XY: 70435 AN XY: 74466

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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

not provided Benign:2

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	clinical testing	Invitae	Feb 01, 2024	- -

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	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T;.;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.60	T;T;.;T
MetaRNN	Benign	0.0000016	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	3.5e-7	P;P;P;P
PrimateAI	Uncertain	0.55	T
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	T
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

Other links and lift over

dbSNP: rs3829462; hg19: chr15-58853079;