rs248

Positions:

• chr8-19953315-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000237.3(LPL):​c.435G>A​(p.Glu145Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,607,244 control chromosomes in the GnomAD database, including 3,772 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (307 hom., cov: 33)
  • Exomes 𝑓: 0.066 (3465 hom.)
• Consequence: LPL NM_000237.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.415

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 8-19953315-G-A is Benign according to our data. Variant chr8-19953315-G-A is described in ClinVar as [Benign]. Clinvar id is 362409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19953315-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.415 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3	c.435G>A	p.Glu145Glu	synonymous_variant	4/10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.435G>A	p.Glu145Glu	synonymous_variant	4/10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000520959.5	c.207G>A	p.Glu69Glu	synonymous_variant	4/5	4		ENSP00000428496.1

Frequencies

GnomAD3 genomes AF: 0.0569 AC: 8666 AN: 152170 Hom.: 307 Cov.: 33

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0314

Gnomad FIN AF: 0.0470

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0758

Gnomad OTH AF: 0.0468

GnomAD3 exomes AF: 0.0499 AC: 12534 AN: 251356 Hom.: 405 AF XY: 0.0502 AC XY: 6822 AN XY: 135844

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.0237

Gnomad ASJ exome AF: 0.0402

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0316

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0707

Gnomad OTH exome AF: 0.0515

GnomAD4 exome AF: 0.0662 AC: 96344 AN: 1454956 Hom.: 3465 Cov.: 29 AF XY: 0.0651 AC XY: 47126 AN XY: 724362

Gnomad4 AFR exome AF: 0.0487

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.0371

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0316

Gnomad4 FIN exome AF: 0.0573

Gnomad4 NFE exome AF: 0.0749

Gnomad4 OTH exome AF: 0.0631

GnomAD4 genome AF: 0.0569 AC: 8660 AN: 152288 Hom.: 307 Cov.: 33 AF XY: 0.0540 AC XY: 4022 AN XY: 74468

Gnomad4 AFR AF: 0.0502

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0315

Gnomad4 FIN AF: 0.0470

Gnomad4 NFE AF: 0.0758

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0687 Hom.: 275

Bravo AF: 0.0539

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0684

EpiControl AF: 0.0635

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2017	Variant summary: The LPL c.435G>A (p.Glu145Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. Mutation taster predicts it as a polymorphism. 5/5 splice prediction tools predict no significant impact on normal splicing. In addition, ESE finder predicts that this variant may not affect binding of ESE sites. This variant was found in 6226/121336 control chromosomes (201 homozygotes) at a frequency of 0.0513121, which is approximately 15 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), thus this variant is likely a benign polymorphism. This variant was found at an allele frequency higher in controls than in patients with Familial Combined Hyperlipidemia in one study (Gagne_1994) and in one hypertriglyceridemia patient who carried biallelic mutations in GPIHBP1 gene (Buonuomo_2015), both evidences supporting for benign outcome. One clinical diagnostic laboratory (via ClinVar) has classified this variant as likely benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2018	- -

Hyperlipoproteinemia, type I Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2018

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	-0.47
CADD	Benign	4.8
DANN	Benign	0.52

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

Other links and lift over

dbSNP: rs248; hg19: chr8-19810826;