8-19948197-G-A

Position:

chr8-19948197-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000237.3(LPL):c.106G>A(p.Asp36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,866 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★).

Frequency

Genomes: 𝑓 0.022 ( 61 hom., cov: 31)

Exomes 𝑓: 0.016 ( 266 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1B:11O:3

Conservation

PhyloP100: 3.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077874362).

BP6

Variant 8-19948197-G-A is Benign according to our data. Variant chr8-19948197-G-A is described in ClinVar as [Likely_benign, other]. Clinvar id is 1552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19948197-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0222 (3374/152068) while in subpopulation AFR AF= 0.0458 (1900/41482). AF 95% confidence interval is 0.0441. There are 61 homozygotes in gnomad4. There are 1562 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 61 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	2/10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.106G>A	p.Asp36Asn	missense_variant	2/10		NM_000237.3	ENSP00000497642	P1

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

3377

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0459

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0152

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.00190

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0159

Gnomad OTH

AF:

0.0239

GnomAD3 exomes

AF:

0.0141

AC:

3554

AN:

251484

Hom.:

AF XY:

0.0146

AC XY:

1987

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.0466

Gnomad AMR exome

AF:

0.00867

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0145

GnomAD4 exome

AF:

0.0160

AC:

23441

AN:

1461798

Hom.:

266

Cov.:

AF XY:

0.0160

AC XY:

11635

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0489

Gnomad4 AMR exome

AF:

0.00955

Gnomad4 ASJ exome

AF:

0.00624

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.00212

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0154

GnomAD4 genome

AF:

0.0222

AC:

3374

AN:

152068

Hom.:

Cov.:

AF XY:

0.0210

AC XY:

1562

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0458

Gnomad4 AMR

AF:

0.0152

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0123

Gnomad4 FIN

AF:

0.00190

Gnomad4 NFE

AF:

0.0159

Gnomad4 OTH

AF:

0.0232

Alfa

AF:

0.0161

Hom.:

Bravo

AF:

0.0246

TwinsUK

AF:

0.0210

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.0454

AC:

200

ESP6500EA

AF:

0.0177

AC:

152

ExAC

AF:

0.0149

AC:

1811

Asia WGS

AF:

0.00837

AC:

AN:

3478

EpiCase

AF:

0.0165

EpiControl

AF:

0.0218

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Pathogenic:1Benign:11Other:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:3Other:1

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2019	This variant is associated with the following publications: (PMID: 11260209, 8839720, 15049943, 9678774, 28267856, 8872057, 10517255, 8541837, 8199176, 7749858, 26934567, 27055971, 24503134, 24123366, 21146168, 18823627, 12535736, 18922999, 28008009, 10364086) -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 13, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Hyperlipoproteinemia, type I

Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency, association with hyperlipidemia. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2019

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. -

LPL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Coronary heart disease

Other:1

risk factor, no assertion criteria provided

clinical testing

Blueprint Genetics

Sep 15, 2014

- -

Hyperlipidemia, familial combined, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

T;.;D;D

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;D;.;D

MetaRNN

Benign

0.0078

T;T;T;T

MetaSVM

Uncertain

-0.28

MutationAssessor

Uncertain

2.1

.;.;M;M

MutationTaster

Benign

0.42

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.5

N;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.063

T;T;T;.

Sift4G

Uncertain

0.058

T;T;T;.

Polyphen

0.074

.;.;B;B

Vest4

0.055

MPC

0.089

ClinPred

0.022

GERP RS

4.3

Varity_R

0.24

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over