rs6078

Variant names:

• chr15-58541794-G-A
• rs6078
• NM_000236.3:c.283G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-58541794-G-A
• chr15-58541794-G-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.283G>A​(p.Val95Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,264 control chromosomes in the GnomAD database, including 3,759 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V95L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.059 (504 hom., cov: 32)
  • Exomes 𝑓: 0.044 (3255 hom.)
• Consequence: LIPC NM_000236.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.976
• Publications: 41 publications found

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016957223).
• BP6: Variant 15-58541794-G-A is Benign according to our data. Variant chr15-58541794-G-A is described in ClinVar as Benign. ClinVar VariationId is 316656.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LIPC	NM_000236.3	c.283G>A	p.Val95Met	missense_variant	Exon 3 of 9	ENST00000299022.10	NP_000227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LIPC	ENST00000299022.10	c.283G>A	p.Val95Met	missense_variant	Exon 3 of 9	1	NM_000236.3	ENSP00000299022.5

Frequencies

GnomAD3 genomes AF: 0.0584 AC: 8890 AN: 152096 Hom.: 502 Cov.: 32

Gnomad AFR AF: 0.0730

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.111

Gnomad FIN AF: 0.0563

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0297

Gnomad OTH AF: 0.0522

GnomAD2 exomes AF: 0.0714 AC: 17826 AN: 249720 AF XY: 0.0696

Gnomad AFR exome AF: 0.0764

Gnomad AMR exome AF: 0.0711

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.333

Gnomad FIN exome AF: 0.0541

Gnomad NFE exome AF: 0.0297

Gnomad OTH exome AF: 0.0476

GnomAD4 exome AF: 0.0443 AC: 64709 AN: 1461048 Hom.: 3255 Cov.: 33 AF XY: 0.0455 AC XY: 33089 AN XY: 726764

African (AFR) AF: 0.0767 AC: 2568 AN: 33462

American (AMR) AF: 0.0670 AC: 2991 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0205 AC: 535 AN: 26118

East Asian (EAS) AF: 0.288 AC: 11428 AN: 39662

South Asian (SAS) AF: 0.102 AC: 8769 AN: 86094

European-Finnish (FIN) AF: 0.0555 AC: 2951 AN: 53178

Middle Eastern (MID) AF: 0.0247 AC: 141 AN: 5700

European-Non Finnish (NFE) AF: 0.0287 AC: 31895 AN: 1111818

Other (OTH) AF: 0.0568 AC: 3431 AN: 60372

GnomAD4 genome AF: 0.0587 AC: 8929 AN: 152216 Hom.: 504 Cov.: 32 AF XY: 0.0629 AC XY: 4684 AN XY: 74432

African (AFR) AF: 0.0735 AC: 3052 AN: 41524

American (AMR) AF: 0.0523 AC: 800 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0251 AC: 87 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1660 AN: 5158

South Asian (SAS) AF: 0.111 AC: 535 AN: 4818

European-Finnish (FIN) AF: 0.0563 AC: 597 AN: 10610

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2024 AN: 68022

Other (OTH) AF: 0.0578 AC: 122 AN: 2110

Alfa AF: 0.0438 Hom.: 1069

Bravo AF: 0.0607

TwinsUK AF: 0.0297 AC: 110

ALSPAC AF: 0.0291 AC: 112

ESP6500AA AF: 0.0746 AC: 327

ESP6500EA AF: 0.0278 AC: 239

ExAC AF: 0.0700 AC: 8500

Asia WGS AF: 0.235 AC: 815 AN: 3478

EpiCase AF: 0.0263

EpiControl AF: 0.0287

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Dec 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31619059, 10924721, 19428034, 24503134) -

Feb 02, 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

- -

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	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.0010
DANN	Benign	0.077
DEOGEN2	Benign	0.31	T;.;T
Eigen	Benign	-3.2
Eigen_PC	Benign	-3.2
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.075	T;T;.
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.0	N;.;N
PhyloP100		-0.98
PrimateAI	Benign	0.25	T
PROVEAN	Benign	2.0	N;N;N
REVEL	Benign	0.19
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.12	B;.;B
Vest4		0.082
MPC		0.072
ClinPred		0.013	T
GERP RS		-9.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.028
gMVP		0.27
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs6078; hg19: chr15-58833993; COSMIC: COSV54421844;