8-19953304-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000237.3(LPL):c.430-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,576,400 control chromosomes in the GnomAD database, including 73 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 57 hom. )

Consequence

LPL
NM_000237.3 splice_region, intron

Scores

Splicing: ADA: 0.001226

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.395

Publications

1 publications found

Variant links:

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

LPL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 8-19953304-C-T is Benign according to our data. Variant chr8-19953304-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00459 (699/152204) while in subpopulation AMR AF = 0.034 (520/15288). AF 95% confidence interval is 0.0316. There are 16 homozygotes in GnomAd4. There are 419 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR,AD gene

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.430-6C>T		splice_region intron	N/A	NP_000228.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.430-6C>T		splice_region intron	N/A	ENSP00000497642.1
	LPL	ENST00000520959.5	TSL:4	c.202-6C>T		splice_region intron	N/A	ENSP00000428496.1

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0337

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00827

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00595

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00789

AC:

1983

AN:

251344

AF XY:

0.00614

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00386

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00221

AC:

3143

AN:

1424196

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1396

AN XY:

710946

show subpopulations

African (AFR)

AF:

0.000398

AC:

AN:

32682

American (AMR)

AF:

0.0461

AC:

2061

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25882

East Asian (EAS)

AF:

0.0101

AC:

398

AN:

39462

South Asian (SAS)

AF:

0.000351

AC:

AN:

85576

European-Finnish (FIN)

AF:

0.00714

AC:

381

AN:

53360

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.000121

AC:

130

AN:

1077852

Other (OTH)

AF:

0.00219

AC:

129

AN:

59000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

149

298

447

596

745

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00459

AC:

699

AN:

152204

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.000722

AC:

AN:

41526

American (AMR)

AF:

0.0340

AC:

520

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00829

AC:

AN:

5190

South Asian (SAS)

AF:

0.000830

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00595

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000412

AC:

AN:

68004

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00364

Hom.:

Bravo

AF:

0.00628

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 07, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The LPL c.430-6C>T variant involves the alteration of a non-conserved intronic nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 731/121160 control chromosomes (15 homozygotes) including ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.051182 (589/11508). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), thus this is likely a benign polymorphism found primarily in the populations of Latino origin. It has also been reported in hypertriglyceridemia patients but without evidence of causality and functional assay indicated that this variant does not affect gene splicing (Nakamura_1996). One clinical diagnostic laboratory (via ClinVar) has classified this variant as likely benign. Taken together, this variant is classified as benign.

Feb 26, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27055971, 9225235)

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Jul 24, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hyperlipoproteinemia, type I

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

8.8

(source)

DANN

Benign

0.80

PhyloP100

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.034

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over