NM_000237.3:c.405G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000237.3(LPL):c.405G>A(p.Val135Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 1,614,046 control chromosomes in the GnomAD database, including 1,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.055 ( 347 hom., cov: 32)

Exomes 𝑓: 0.032 ( 998 hom. )

Consequence

LPL
NM_000237.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.537

Publications

25 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 8-19951924-G-A is Benign according to our data. Variant chr8-19951924-G-A is described in ClinVar as Benign. ClinVar VariationId is 362407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.537 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.405G>A	p.Val135Val	synonymous_variant	Exon 3 of 10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 link	c.405G>A	p.Val135Val	synonymous_variant	Exon 3 of 10		NM_000237.3	ENSP00000497642.1		P06858

Frequencies

GnomAD3 genomes

AF:

0.0546

AC:

8298

AN:

152076

Hom.:

346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.111

Gnomad AMI

AF:

0.0515

Gnomad AMR

AF:

0.0420

Gnomad ASJ

AF:

0.0657

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00932

Gnomad FIN

AF:

0.0347

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0331

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0332

AC:

8353

AN:

251430

AF XY:

0.0313

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.0252

Gnomad ASJ exome

AF:

0.0661

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0290

Gnomad NFE exome

AF:

0.0334

Gnomad OTH exome

AF:

0.0334

GnomAD4 exome

AF:

0.0320

AC:

46818

AN:

1461852

Hom.:

998

Cov.:

AF XY:

0.0316

AC XY:

22997

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.116

AC:

3877

AN:

33478

American (AMR)

AF:

0.0262

AC:

1170

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

1649

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0107

AC:

926

AN:

86256

European-Finnish (FIN)

AF:

0.0266

AC:

1421

AN:

53420

Middle Eastern (MID)

AF:

0.0621

AC:

358

AN:

5768

European-Non Finnish (NFE)

AF:

0.0317

AC:

35198

AN:

1111974

Other (OTH)

AF:

0.0367

AC:

2219

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

2511

5023

7534

10046

12557

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1368

2736

4104

5472

6840

<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:

0.0546

AC:

8317

AN:

152194

Hom.:

347

Cov.:

AF XY:

0.0535

AC XY:

3977

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.111

AC:

4621

AN:

41518

American (AMR)

AF:

0.0420

AC:

641

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0657

AC:

228

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00912

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0347

AC:

368

AN:

10592

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0331

AC:

2251

AN:

68024

Other (OTH)

AF:

0.0441

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

377

754

1130

1507

1884

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<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:

0.0435

Hom.:

312

Bravo

AF:

0.0577

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0388

EpiControl

AF:

0.0406

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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.405G>A (p.Val135Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SF2/ASF. This variant was found in 4195/121380 control chromosomes (117 homozygotes) from ExAC, predominantly observed in the African subpopulation at a frequency of 0.116997 (1217/10402). This frequency is about 35 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), thus this is a benign polymorphism found primarily in the populations of African origin. This variant was also not associated with Type 2 diabetes or lowered HDL-C levels in a case-control study from India (Ayyappa_2017). One clinical laboratory (via ClinVar) has classified this variant as likely benign. Taken together, this variant is classified as benign. -

not specified

Benign:1

Apr 09, 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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dystrophin deficiency

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Feb 03, 2019

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

6.0

(source)

DANN

Benign

0.59

PhyloP100

-0.54

Splicing

Name

Calibrated prediction

Score

Prediction

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over