Genetic Variant NM_000237.3:c.5A>T (chr8-19939445-A-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000237.3(LPL):c.5A>T(p.Glu2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,608,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.686

Publications

2 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: Uncertain_significance. The variant received 1 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.5A>T	p.Glu2Val	missense_variant	Exon 1 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.5A>T	p.Glu2Val	missense_variant	Exon 1 of 10		NM_000237.3	ENSP00000497642.1		P06858

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000195

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

238532

AF XY:

0.0000154

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457118

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.0000759

AC:

AN:

39540

South Asian (SAS)

AF:

0.00

AC:

AN:

85578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110312

Other (OTH)

AF:

0.0000332

AC:

AN:

60186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151802

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41318

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000195

AC:

AN:

5118

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0082

T;.;T;T

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.72

T;T;.;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.7

.;.;L;L

PhyloP100

0.69

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.1

N;N;N;.

REVEL

Benign

0.23

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.0080

D;D;T;.

Polyphen

0.82

.;.;P;P

Vest4

0.14

MutPred

0.29

Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);

MVP

0.93

MPC

0.16

ClinPred

0.26

GERP RS

1.5

PromoterAI

0.10

Neutral

(source)

Varity_R

0.11

gMVP

0.74

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -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

Computational scores

Splicing

Publications

Other links and lift over