rs6080

chr15-58545734-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000236.3(LIPC):c.575-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0338 in 1,613,420 control chromosomes in the GnomAD database, including 1,069 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (71 hom., cov: 34)
  • Exomes 𝑓: 0.035 (998 hom.)
• Consequence: LIPC NM_000236.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.002304
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.48

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 (BayesDel_noAF=-0.76).
• BP6: Variant 15-58545734-C-A is Benign according to our data. Variant chr15-58545734-C-A is described in ClinVar as [Benign]. Clinvar id is 316661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-58545734-C-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0257 (3908/152340) while in subpopulation NFE AF= 0.0372 (2533/68040). AF 95% confidence interval is 0.036. There are 71 homozygotes in gnomad4. There are 1874 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 71 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPC	NM_000236.3	c.575-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000299022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPC	ENST00000299022.10	c.575-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000236.3	P1

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3910 AN: 152224 Hom.: 71 Cov.: 34

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0324

Gnomad ASJ AF: 0.0397

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0372

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0281 AC: 7047 AN: 250942 Hom.: 133 AF XY: 0.0294 AC XY: 3990 AN XY: 135698

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.0191

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0322

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0336

GnomAD4 exome AF: 0.0347 AC: 50665 AN: 1461080 Hom.: 998 Cov.: 34 AF XY: 0.0349 AC XY: 25394 AN XY: 726912

Gnomad4 AFR exome AF: 0.00616

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.0411

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0384

Gnomad4 OTH exome AF: 0.0331

GnomAD4 genome AF: 0.0257 AC: 3908 AN: 152340 Hom.: 71 Cov.: 34 AF XY: 0.0252 AC XY: 1874 AN XY: 74482

Gnomad4 AFR AF: 0.00683

Gnomad4 AMR AF: 0.0323

Gnomad4 ASJ AF: 0.0397

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0288

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0372

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.0316 Hom.: 44

Bravo AF: 0.0253

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0410

EpiControl AF: 0.0436

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 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2019	- -

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	-0.76
Cadd	Benign	6.3
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0023
dbscSNV1_RF	Benign	0.056
SpliceAI score (max)		0.030		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: rs6080; hg19: chr15-58837933;