chr8-19961040-G-A

Position:

chr8-19961040-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.1279G>A(p.Ala427Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00209 in 1,614,058 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 24 hom. )

Consequence

LPL
NM_000237.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.269

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=0.005454719).

BP6

Variant 8-19961040-G-A is Benign according to our data. Variant chr8-19961040-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 362414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19961040-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00889 (1354/152240) while in subpopulation AFR AF= 0.0295 (1226/41542). AF 95% confidence interval is 0.0281. There are 16 homozygotes in gnomad4. There are 645 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.1279G>A	p.Ala427Thr	missense_variant	8/10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	ENST00000650287.1 link	c.1279G>A	p.Ala427Thr	missense_variant	8/10	NM_000237.3	ENSP00000497642.1	P06858
LPL	ENST00000650478.1 link	n.*102G>A		non_coding_transcript_exon_variant	2/4		ENSP00000497560.1	A0A3B3IT60
LPL	ENST00000650478.1 link	n.*102G>A		3_prime_UTR_variant	2/4		ENSP00000497560.1	A0A3B3IT60

Frequencies

GnomAD3 genomes

AF:

0.00891

AC:

1355

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.0141

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.00313

AC:

787

AN:

251196

Hom.:

AF XY:

0.00269

AC XY:

365

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.0298

Gnomad AMR exome

AF:

0.00185

Gnomad ASJ exome

AF:

0.0174

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000359

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000299

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00138

AC:

2015

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

949

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0300

Gnomad4 AMR exome

AF:

0.00215

Gnomad4 ASJ exome

AF:

0.0188

Gnomad4 EAS exome

AF:

0.000479

Gnomad4 SAS exome

AF:

0.000336

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000163

Gnomad4 OTH exome

AF:

0.00296

GnomAD4 genome

AF:

0.00889

AC:

1354

AN:

152240

Hom.:

Cov.:

AF XY:

0.00867

AC XY:

645

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0295

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.0141

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000220

Gnomad4 OTH

AF:

0.00521

Alfa

AF:

0.00300

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0259

AC:

114

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00326

AC:

396

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2021	This variant is associated with the following publications: (PMID: 25966443, 22239554) -

Hyperlipoproteinemia, type I

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 25, 2019	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 06, 2022

Variant summary: LPL c.1279G>A (p.Ala427Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 252692 control chromosomes, predominantly at a frequency of 0.03 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1279G>A has been reported in the literature in individuals affected with Familial Lipoprotein Lipase Deficiency or hypertriglyceridemia. These reports do not provide unequivocal conclusions about association of the variant with Familial Lipoprotein Lipase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Surendran_2012). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3) /likely benign (n=1). Based on the evidence outlined above, the variant was classified as benign. -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2020

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

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

4.4

DANN

Benign

0.36

DEOGEN2

Benign

0.076

T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.088

LIST_S2

Benign

0.14

.;T

MetaRNN

Benign

0.0055

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.71

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.39

N;.

REVEL

Benign

0.13

Sift

Benign

0.60

T;.

Sift4G

Benign

0.65

T;.

Polyphen

0.0

B;B

Vest4

0.10

MVP

0.62

MPC

0.075

ClinPred

0.00013

GERP RS

-0.38

Varity_R

0.058

gMVP

0.50

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