rs6080

Variant names:

• chr15-58545734-C-A
• rs6080
• NM_000236.3:c.575-8C>A

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.002304
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.48
• Publications: 10 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 316661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 71 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000236.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPC	NM_000236.3	MANE Select	c.575-8C>A		splice_region intron	N/A	NP_000227.2	P11150

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LIPC	ENST00000299022.10	TSL:1 MANE Select	c.575-8C>A		splice_region intron	N/A	ENSP00000299022.5	P11150
	LIPC	ENST00000414170.7	TSL:1	c.575-8C>A		splice_region intron	N/A	ENSP00000395569.3	E7EUJ1
	LIPC	ENST00000559845.5	TSL:1	n.432-8C>A		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.0281 AC: 7047 AN: 250942 AF XY: 0.0294

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 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

African (AFR) AF: 0.00616 AC: 206 AN: 33466

American (AMR) AF: 0.0201 AC: 897 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0411 AC: 1075 AN: 26124

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39696

South Asian (SAS) AF: 0.0316 AC: 2728 AN: 86236

European-Finnish (FIN) AF: 0.0145 AC: 773 AN: 53370

Middle Eastern (MID) AF: 0.0491 AC: 283 AN: 5760

European-Non Finnish (NFE) AF: 0.0384 AC: 42696 AN: 1111334

Other (OTH) AF: 0.0331 AC: 1999 AN: 60370

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

African (AFR) AF: 0.00683 AC: 284 AN: 41576

American (AMR) AF: 0.0323 AC: 495 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 138 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0288 AC: 139 AN: 4826

European-Finnish (FIN) AF: 0.0146 AC: 155 AN: 10618

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0372 AC: 2533 AN: 68040

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0319 Hom.: 51

Bravo AF: 0.0253

Asia WGS AF: 0.0140 AC: 50 AN: 3478

EpiCase AF: 0.0410

EpiControl AF: 0.0436

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hyperlipidemia due to hepatic triglyceride lipase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.3
DANN	Benign	0.68
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6080; hg19: chr15-58837933; COSMIC: COSV107334516;