rs248

Variant names:

• chr8-19953315-G-A
• rs248
• NM_000237.3:c.435G>A

Variant summary

Our verdict is Benign. The variant received -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:8
• Conservation: PhyloP100: 0.415
• Publications: 28 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 362409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.435G>A	p.Glu145Glu	synonymous_variant	Exon 4 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.435G>A	p.Glu145Glu	synonymous_variant	Exon 4 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000520959.5	c.207G>A	p.Glu69Glu	synonymous_variant	Exon 4 of 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

GnomAD2 exomes AF: 0.0499 AC: 12534 AN: 251356 AF XY: 0.0502

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 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

African (AFR) AF: 0.0487 AC: 1626 AN: 33364

American (AMR) AF: 0.0256 AC: 1144 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0371 AC: 968 AN: 26082

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39652

South Asian (SAS) AF: 0.0316 AC: 2720 AN: 86150

European-Finnish (FIN) AF: 0.0573 AC: 3059 AN: 53390

Middle Eastern (MID) AF: 0.0357 AC: 206 AN: 5766

European-Non Finnish (NFE) AF: 0.0749 AC: 82820 AN: 1105672

Other (OTH) AF: 0.0631 AC: 3798 AN: 60168

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

African (AFR) AF: 0.0502 AC: 2086 AN: 41564

American (AMR) AF: 0.0328 AC: 502 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4830

European-Finnish (FIN) AF: 0.0470 AC: 498 AN: 10598

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0758 AC: 5156 AN: 68020

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0686 Hom.: 381

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:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Oct 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperlipoproteinemia, type I Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 11, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.41

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

Other links and lift over

dbSNP: rs248; hg19: chr8-19810826;