chr8-19962213-C-G

Variant names:

• chr8-19962213-C-G
• rs328
• NM_000237.3:c.1421C>G
• LPL p.Ser474*

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -10 classification points (ACMG Germline Pathogenicity v2019). BA1PVS1_ModerateBP6_Strong

The NM_000237.3(LPL):c.1421C>G (p.Ser474*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. This is a loss-of-function variant that does not trigger NMD. The variant allele was found at a cumulative frequency of 0.0968 (AC=156,015) in the gnomAD database across 1,611,322 control chromosomes, including 7,879 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.119. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (610 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7269 hom.)
• Consequence: LPL NM_000237.3 stop_gained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.429
• Publications: 451 publications found

Genes affected

LPL (HGNC:6677): (lipoprotein lipase) LPL encodes lipoprotein lipase, which is expressed in heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism. [provided by RefSeq, Jul 2008]

LPL Gene-Disease associations (from GenCC):

• familial lipoprotein lipase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Natera, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• hyperlipidemia, familial combined, LPL related

  Inheritance: AD, SD, Unknown Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, PanelApp Australia, Natera

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Non-NMD frameshift: disease mechanism, end-terminal — moderate (PVS1 downgraded to PM); Stop-gained (exon 9 of 10) at amino acid 474 of 475; NMD not predicted. Loss of function is a known disease mechanism, though the variant is in the terminal region of the CDS.
	BP6Reputable source reports benign		ClinVar 2-star benign — strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 2 star(s). ClinVar submissions strongly and reliably favor benignity (11/11 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1192 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000237.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LPL NM_000237.3	MANE Select	c.1421C>G p.Ser474*	stop_gained	Exon 9 of 10	Prot: NP_000228.1 UniProt:

LPL NM_000237.3

MANE Select

HGVSc / HGVSpc.1421C>Gp.Ser474*

Exon rankExon 9 of 10

stop_gained

Prot: NP_000228.1UniProt: P06858

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LPL ENST00000650287.1	MANE Select	c.1421C>G p.Ser474*	stop_gained	Exon 9 of 10	Prot: ENSP00000497642.1 UniProt:
	LPL ENST00000965928.1		c.1421C>G p.Ser474*	stop_gained	Exon 11 of 12	Prot: ENSP00000635987.1 UniProt:
	LPL ENST00000965929.1		c.1418C>G p.Ser473*	stop_gained	Exon 9 of 10	Prot: ENSP00000635988.1 UniProt:

LPL ENST00000650287.1

MANE Select

HGVSc / HGVSpc.1421C>Gp.Ser474*

Exon rankExon 9 of 10

stop_gained

Prot: ENSP00000497642.1UniProt: P06858

LPL ENST00000965928.1

HGVSc / HGVSpc.1421C>Gp.Ser474*

Exon rankExon 11 of 12

stop_gained

Prot: ENSP00000635987.1UniProt: P06858

LPL ENST00000965929.1

HGVSc / HGVSpc.1418C>Gp.Ser473*

Exon rankExon 9 of 10

stop_gained

Prot: ENSP00000635988.1UniProt: A0ACI8VCL6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0902	AC:13720	Hom:611	AN:152082	Cov:32
GnomAD2 exomes	AF: 0.0922	AC:23148	Hom:	AN:251182	Cov:
GnomAD4 exome	AF: 0.0975	AC:142308	Hom:7269	AN:1459122	Cov:31
GnomAD4 genome	AF: 0.0901	AC:13707	Hom:610	AN:152200	Cov:32
TOPMed (Bravo)	AF: 0.0879	AC:23273	Hom:1103	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0990	AC:12022	Hom:621	AN:121420	Cov:
Local & regional cohorts 11 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.0944	AC:221	Hom:15	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0912	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.120	AC:36	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.0863	AC:1123	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.100	AC:346	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.116	AC:840	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.0825	AC:165	Hom:	AN:2000	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.131	AC:16028	Hom:1040	AN:122780	Cov:
Turkish Variome	AF: 0.104	AC:698	Hom:43	AN:6708	Cov:
UK10K	AF: 0.107	AC:811	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.102	AC:917	Hom:53	AN:8960	Cov:

Showing 17 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.0963 *	1070	11108	0.100 *	1768	17610
BipEx(Bipolar disorder (including schizoaffective))	0.0976	2773	28420	0.0971	2802	28844
Epi25(Epilepsy)	0.101	4233	41946	0.0927	6170	66536
SCHEMA(Schizophrenia)	0.105	13524	128696	0.107	21829	203540

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hyperlipoproteinemia, type I (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I (1)
-	-	1	LPL-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	46
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Benign	0.70	D
GPN-Star LLR	N/A	-9.4
GPN-Star score	N/A	9.4
PhyloP100	Benign	0.43

Showing 11 of 11 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DG_spliceai	Uncertain	0.20	Position offset: -3
Pangolin (max)	Uncertain	0.23
Pangolin loss	Uncertain	0.23	Position offset: 6
SpliceAI score (max)	Uncertain	0.20	Details are displayed if max score is > 0.2

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs328;

hg19: chr8-19819724;

COSMIC: COSV60930552;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar