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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000237.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.435G>A	p.Glu145Glu	synonymous	Exon 4 of 10	NP_000228.1	P06858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.435G>A	p.Glu145Glu	synonymous	Exon 4 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.435G>A	p.Glu145Glu	synonymous	Exon 6 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.432G>A	p.Glu144Glu	splice_region synonymous	Exon 4 of 10	ENSP00000635988.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Hyperlipoproteinemia, type I (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;