NM_000236.3:c.644A>G

Variant names:

• chr15-58545811-A-G
• rs6083
• NM_000236.3:c.644A>G

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.644A>G​(p.Asn215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 1,613,832 control chromosomes in the GnomAD database, including 150,437 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19950 hom., cov: 33)
  • Exomes 𝑓: 0.41 (130487 hom.)
• Consequence: LIPC NM_000236.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.06
• Publications: 70 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 (MetaRNN=9.311974E-6).
• BP6: Variant 15-58545811-A-G is Benign according to our data. Variant chr15-58545811-A-G is described in ClinVar as Benign. ClinVar VariationId is 316665.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

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.644A>G	p.Asn215Ser	missense	Exon 5 of 9	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.644A>G	p.Asn215Ser	missense	Exon 5 of 9	ENSP00000299022.5	P11150
	LIPC	ENST00000414170.7	TSL:1	c.644A>G	p.Asn215Ser	missense	Exon 6 of 10	ENSP00000395569.3	E7EUJ1
	LIPC	ENST00000559845.5	TSL:1	n.501A>G		non_coding_transcript_exon	Exon 4 of 7

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74031 AN: 151956 Hom.: 19910 Cov.: 33

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.483

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.438

GnomAD2 exomes AF: 0.473 AC: 118936 AN: 251460 AF XY: 0.464

Gnomad AFR exome AF: 0.680

Gnomad AMR exome AF: 0.548

Gnomad ASJ exome AF: 0.326

Gnomad EAS exome AF: 0.830

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.407 AC: 595410 AN: 1461758 Hom.: 130487 Cov.: 58 AF XY: 0.409 AC XY: 297505 AN XY: 727188

African (AFR) AF: 0.687 AC: 22995 AN: 33480

American (AMR) AF: 0.543 AC: 24264 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8624 AN: 26136

East Asian (EAS) AF: 0.882 AC: 35020 AN: 39698

South Asian (SAS) AF: 0.550 AC: 47446 AN: 86254

European-Finnish (FIN) AF: 0.483 AC: 25818 AN: 53418

Middle Eastern (MID) AF: 0.346 AC: 1996 AN: 5766

European-Non Finnish (NFE) AF: 0.363 AC: 403790 AN: 1111890

Other (OTH) AF: 0.422 AC: 25457 AN: 60392

GnomAD4 genome AF: 0.487 AC: 74126 AN: 152074 Hom.: 19950 Cov.: 33 AF XY: 0.495 AC XY: 36811 AN XY: 74322

African (AFR) AF: 0.674 AC: 27965 AN: 41494

American (AMR) AF: 0.489 AC: 7485 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1151 AN: 3468

East Asian (EAS) AF: 0.830 AC: 4283 AN: 5160

South Asian (SAS) AF: 0.564 AC: 2716 AN: 4814

European-Finnish (FIN) AF: 0.483 AC: 5104 AN: 10572

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.355 AC: 24145 AN: 67960

Other (OTH) AF: 0.444 AC: 936 AN: 2110

Alfa AF: 0.397 Hom.: 49222

Bravo AF: 0.497

TwinsUK AF: 0.362 AC: 1343

ALSPAC AF: 0.364 AC: 1402

ESP6500AA AF: 0.678 AC: 2974

ESP6500EA AF: 0.363 AC: 3117

ExAC AF: 0.470 AC: 57087

Asia WGS AF: 0.686 AC: 2382 AN: 3478

EpiCase AF: 0.342

EpiControl AF: 0.342

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Hyperlipidemia due to hepatic triglyceride lipase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.7
DANN	Benign	0.95
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.051	T
MetaRNN	Benign	0.0000093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L
PhyloP100		2.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.17
Sift	Benign	0.055	T
Sift4G	Benign	0.36	T
Polyphen		0.0030	B
Vest4		0.022
MPC		0.060
ClinPred		0.0072	T
GERP RS		-0.071
Varity_R		0.11
gMVP		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6083; hg19: chr15-58838010; COSMIC: COSV54420926;