chr8-19962213-C-A

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PVS1_ModeratePM2BP6_Moderate

The NM_000237.3(LPL):c.1421C>A (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 0.00000205 (AC=3) in the gnomAD database across 1,460,822 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Variant has been reported in ClinVar as Benign/Likely Benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: LPL NM_000237.3 stop_gained
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.429
• Publications: 746 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: Uncertain_significance. The variant received 2 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.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000116 — very rare for AD+AR gene (base 0.0001, raised to 0.000356 by highest known P/LP ClinVar AF 0.000356) — PM2 moderate.
	BP6Reputable source reports benign		ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

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>A p.Ser474*	stop_gained	Exon 9 of 10	Prot: NP_000228.1 UniProt:

LPL NM_000237.3

MANE Select

HGVSc / HGVSpc.1421C>Ap.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>A p.Ser474*	stop_gained	Exon 9 of 10	Prot: ENSP00000497642.1 UniProt:
	LPL ENST00000965928.1		c.1421C>A p.Ser474*	stop_gained	Exon 11 of 12	Prot: ENSP00000635987.1 UniProt:
	LPL ENST00000965929.1		c.1418C>A p.Ser473*	stop_gained	Exon 9 of 10	Prot: ENSP00000635988.1 UniProt:

LPL ENST00000650287.1

MANE Select

HGVSc / HGVSpc.1421C>Ap.Ser474*

Exon rankExon 9 of 10

stop_gained

Prot: ENSP00000497642.1UniProt: P06858

LPL ENST00000965928.1

HGVSc / HGVSpc.1421C>Ap.Ser474*

Exon rankExon 11 of 12

stop_gained

Prot: ENSP00000635987.1UniProt: P06858

LPL ENST00000965929.1

HGVSc / HGVSpc.1418C>Ap.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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000205	AC:3	Hom:0	AN:1460822	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000151	1	66408	0.00	0	130382

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	62
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	55
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Benign	0.72	D
GPN-Star LLR	N/A	-9.9
GPN-Star score	N/A	9.9
PhyloP100	Benign	0.43

Showing 11 of 11 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
DS_DG_spliceai	Pathogenic	0.85	Position offset: -3
Pangolin (max)	Pathogenic	0.61
Pangolin gain	Pathogenic	0.61	Position offset: -3
Pangolin loss	Uncertain	0.24	Position offset: 6
SpliceAI score (max)	Pathogenic	0.85	Details are displayed if max score is > 0.2

Showing 5 of 5 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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar