Genetic Variant NM_000237.3:c.775+103C>T (chr8-19954456-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000237.3(LPL):c.775+103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,154,498 control chromosomes in the GnomAD database, including 12,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1379 hom., cov: 33)

Exomes 𝑓: 0.15 ( 10828 hom. )

Consequence

LPL
NM_000237.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.529

Publications

29 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 8-19954456-C-T is Benign according to our data. Variant chr8-19954456-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.775+103C>T		intron_variant	Intron 5 of 9	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 link	c.775+103C>T		intron_variant	Intron 5 of 9		NM_000237.3	ENSP00000497642.1		P06858

Frequencies

GnomAD3 genomes

AF:

0.124

AC:

18831

AN:

152110

Hom.:

1375

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0621

Gnomad AMI

AF:

0.207

Gnomad AMR

AF:

0.153

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.222

Gnomad SAS

AF:

0.183

Gnomad FIN

AF:

0.102

Gnomad MID

AF:

0.136

Gnomad NFE

AF:

0.143

Gnomad OTH

AF:

0.126

GnomAD4 exome

AF:

0.145

AC:

145604

AN:

1002270

Hom.:

10828

AF XY:

0.147

AC XY:

75054

AN XY:

510676

show subpopulations

African (AFR)

AF:

0.0596

AC:

1410

AN:

23660

American (AMR)

AF:

0.146

AC:

5183

AN:

35448

Ashkenazi Jewish (ASJ)

AF:

0.174

AC:

3850

AN:

22190

East Asian (EAS)

AF:

0.215

AC:

7486

AN:

34888

South Asian (SAS)

AF:

0.179

AC:

12706

AN:

70920

European-Finnish (FIN)

AF:

0.103

AC:

4966

AN:

48252

Middle Eastern (MID)

AF:

0.124

AC:

591

AN:

4778

European-Non Finnish (NFE)

AF:

0.144

AC:

103115

AN:

717132

Other (OTH)

AF:

0.140

AC:

6297

AN:

45002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

6029

12058

18086

24115

30144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3150

6300

9450

12600

15750

<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:

0.124

AC:

18832

AN:

152228

Hom.:

1379

Cov.:

AF XY:

0.125

AC XY:

9320

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0620

AC:

2575

AN:

41548

American (AMR)

AF:

0.153

AC:

2346

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

598

AN:

3468

East Asian (EAS)

AF:

0.221

AC:

1141

AN:

5156

South Asian (SAS)

AF:

0.183

AC:

883

AN:

4820

European-Finnish (FIN)

AF:

0.102

AC:

1082

AN:

10612

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.143

AC:

9709

AN:

68020

Other (OTH)

AF:

0.128

AC:

271

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

846

1692

2538

3384

4230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.141

Hom.:

3849

Bravo

AF:

0.122

Asia WGS

AF:

0.197

AC:

683

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 22, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.92

(source)

DANN

Benign

0.48

PhyloP100

-0.53

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