rs6074

chr15-58568764-C-Achr15-58568764-C-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000236.3(LIPC):c.1437C>A(p.Thr479=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,608,476 control chromosomes in the GnomAD database, including 24,583 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T479T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1950 hom., cov: 33)
  • Exomes 𝑓: 0.16 (22633 hom.)
• Consequence: LIPC NM_000236.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.24

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 15-58568764-C-A is Benign according to our data. Variant chr15-58568764-C-A is described in ClinVar as [Benign]. Clinvar id is 316681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-58568764-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPC	NM_000236.3	c.1437C>A	p.Thr479=	synonymous_variant	9/9	ENST00000299022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPC	ENST00000299022.10	c.1437C>A	p.Thr479=	synonymous_variant	9/9	1	NM_000236.3	P1
LIPC	ENST00000356113.10	c.1437C>A	p.Thr479=	synonymous_variant	11/11	2		P1
LIPC	ENST00000433326.2	c.1254C>A	p.Thr418=	synonymous_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22208 AN: 151956 Hom.: 1944 Cov.: 33

Gnomad AFR AF: 0.0915

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.193 AC: 48231 AN: 250016 Hom.: 5626 AF XY: 0.196 AC XY: 26504 AN XY: 135154

Gnomad AFR exome AF: 0.0930

Gnomad AMR exome AF: 0.255

Gnomad ASJ exome AF: 0.0997

Gnomad EAS exome AF: 0.262

Gnomad SAS exome AF: 0.345

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.136

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.165 AC: 239746 AN: 1456404 Hom.: 22633 Cov.: 30 AF XY: 0.169 AC XY: 122784 AN XY: 724748

Gnomad4 AFR exome AF: 0.0945

Gnomad4 AMR exome AF: 0.248

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.281

Gnomad4 SAS exome AF: 0.340

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.152

GnomAD4 genome AF: 0.146 AC: 22216 AN: 152072 Hom.: 1950 Cov.: 33 AF XY: 0.155 AC XY: 11487 AN XY: 74338

Gnomad4 AFR AF: 0.0914

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.104

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.336

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.114

Alfa AF: 0.134 Hom.: 2893

Bravo AF: 0.136

Asia WGS AF: 0.273 AC: 946 AN: 3476

EpiCase AF: 0.129

EpiControl AF: 0.123

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	- -

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	-0.26
Cadd	Benign	2.0
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs6074; hg19: chr15-58860963; COSMIC: COSV54422234; COSMIC: COSV54422234;