rs3829462

Variant names:

• chr15-58560880-C-A
• rs3829462
• NM_000236.3:c.1068C>A

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -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. 13/22 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:6
• 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
LIPC	NM_000236.3	c.1068C>A	p.Phe356Leu	missense_variant	Exon 7 of 9	ENST00000299022.10	NP_000227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPC	ENST00000299022.10	c.1068C>A	p.Phe356Leu	missense_variant	Exon 7 of 9	1	NM_000236.3	ENSP00000299022.5

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

GnomAD2 exomes AF: 0.972 AC: 244028 AN: 251044 AF XY: 0.975

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 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 AC: 22591 AN: 26844

Gnomad4 AMR exome AF: 0.989 AC: 43799 AN: 44264

Gnomad4 ASJ exome AF: 0.998 AC: 23651 AN: 23708

Gnomad4 EAS exome AF: 0.908 AC: 34471 AN: 37944

Gnomad4 SAS exome AF: 0.986 AC: 77211 AN: 78272

Gnomad4 FIN exome AF: 0.948 AC: 50514 AN: 53298

Gnomad4 NFE exome AF: 0.981 AC: 739514 AN: 753490

Gnomad4 Remaining exome AF: 0.972 AC: 46115 AN: 47446

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 AC: 0.857865 AN: 0.857865

Gnomad4 AMR AF: 0.982 AC: 0.981702 AN: 0.981702

Gnomad4 ASJ AF: 0.998 AC: 0.998272 AN: 0.998272

Gnomad4 EAS AF: 0.936 AC: 0.935907 AN: 0.935907

Gnomad4 SAS AF: 0.986 AC: 0.98633 AN: 0.98633

Gnomad4 FIN AF: 0.946 AC: 0.946496 AN: 0.946496

Gnomad4 NFE AF: 0.986 AC: 0.98558 AN: 0.98558

Gnomad4 OTH AF: 0.967 AC: 0.967391 AN: 0.967391

Alfa AF: 0.973 Hom.: 292541

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

Submissions by phenotype

not provided Benign:3

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27884173, 8732782, 20981092, 19428034) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hyperlipidemia due to hepatic triglyceride lipase deficiency Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
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
Mutation Taster		=97/3	polymorphism (auto)

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; COSMIC: COSV107334465;