15-58560910-A-G

Position:

• chr15-58560910-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000236.3(LIPC):​c.1098A>G​(p.Thr366Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.975 in 1,530,340 control chromosomes in the GnomAD database, including 728,244 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68368 hom., cov: 32)
  • Exomes 𝑓: 0.98 (659876 hom.)
• Consequence: LIPC NM_000236.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.123

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 15-58560910-A-G is Benign according to our data. Variant chr15-58560910-A-G is described in ClinVar as [Benign]. Clinvar id is 316674.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-58560910-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• 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	Protein	UniProt
LIPC	NM_000236.3	c.1098A>G	p.Thr366Thr	synonymous_variant	7/9	ENST00000299022.10	NP_000227.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LIPC	ENST00000299022.10	c.1098A>G	p.Thr366Thr	synonymous_variant	7/9	1	NM_000236.3	ENSP00000299022.5

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143958 AN: 152152 Hom.: 68334 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: 0.987

Gnomad FIN AF: 0.947

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.986

Gnomad OTH AF: 0.966

GnomAD3 exomes AF: 0.972 AC: 244309 AN: 251330 Hom.: 118896 AF XY: 0.975 AC XY: 132440 AN XY: 135834

Gnomad AFR exome AF: 0.860

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: 0.978 AC: 1348031 AN: 1378070 Hom.: 659876 Cov.: 25 AF XY: 0.979 AC XY: 675895 AN XY: 690322

Gnomad4 AFR exome AF: 0.855

Gnomad4 AMR exome AF: 0.990

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 0.910

Gnomad4 SAS exome AF: 0.987

Gnomad4 FIN exome AF: 0.948

Gnomad4 NFE exome AF: 0.985

Gnomad4 OTH exome AF: 0.975

GnomAD4 genome AF: 0.946 AC: 144044 AN: 152270 Hom.: 68368 Cov.: 32 AF XY: 0.946 AC XY: 70413 AN XY: 74450

Gnomad4 AFR AF: 0.857

Gnomad4 AMR AF: 0.982

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 0.936

Gnomad4 SAS AF: 0.987

Gnomad4 FIN AF: 0.947

Gnomad4 NFE AF: 0.986

Gnomad4 OTH AF: 0.967

Alfa AF: 0.980 Hom.: 139934

Bravo AF: 0.945

Asia WGS AF: 0.962 AC: 3346 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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

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

Hyperlipidemia due to hepatic triglyceride lipase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.12
DANN	Benign	0.34

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: rs3829461; hg19: chr15-58853109;