rs316

Positions:

• chr8-19960925-C-A
• chr8-19960925-C-G
• chr8-19960925-C-T

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.1164C>A​(p.Thr388=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,612,340 control chromosomes in the GnomAD database, including 14,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2009 hom., cov: 31)
  • Exomes 𝑓: 0.13 (12298 hom.)
• Consequence: LPL NM_000237.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.57

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=-0.75).
• BP6: Variant 8-19960925-C-A is Benign according to our data. Variant chr8-19960925-C-A is described in ClinVar as [Benign]. Clinvar id is 362413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19960925-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3	c.1164C>A	p.Thr388=	synonymous_variant	8/10	ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1	c.1164C>A	p.Thr388=	synonymous_variant	8/10		NM_000237.3	P1
LPL	ENST00000650478.1	c.104C>A	p.Pro35His	missense_variant, NMD_transcript_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23541 AN: 151804 Hom.: 2000 Cov.: 31

Gnomad AFR AF: 0.223

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.0963

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.110

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.135 AC: 33843 AN: 251348 Hom.: 2482 AF XY: 0.133 AC XY: 18048 AN XY: 135840

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.0965

Gnomad SAS exome AF: 0.128

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.127 AC: 185694 AN: 1460422 Hom.: 12298 Cov.: 33 AF XY: 0.127 AC XY: 92390 AN XY: 726602

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.210

Gnomad4 EAS exome AF: 0.0777

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.134

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.155 AC: 23575 AN: 151918 Hom.: 2009 Cov.: 31 AF XY: 0.154 AC XY: 11435 AN XY: 74254

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.200

Gnomad4 EAS AF: 0.0964

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.130

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.144

Alfa AF: 0.129 Hom.: 2097

Bravo AF: 0.157

Asia WGS AF: 0.128 AC: 442 AN: 3478

EpiCase AF: 0.122

EpiControl AF: 0.121

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperlipoproteinemia, type I Benign:2

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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 09, 2023

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 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	-0.75
CADD	Benign	1.4
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs316; hg19: chr8-19818436;