rs295

Variant names:

• chr8-19958727-A-C
• rs295
• NM_000237.3:c.1019-533A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000237.3(LPL):​c.1019-533A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.275 in 152,026 control chromosomes in the GnomAD database, including 6,119 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6119 hom., cov: 31)
• Consequence: LPL NM_000237.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.423
• Publications: 51 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.1019-533A>C		intron_variant	Intron 6 of 9	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.1019-533A>C		intron_variant	Intron 6 of 9		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.80-2174A>C		intron_variant	Intron 1 of 3			ENSP00000497560.1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41763 AN: 151908 Hom.: 6108 Cov.: 31

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.256

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.275 AC: 41796 AN: 152026 Hom.: 6119 Cov.: 31 AF XY: 0.272 AC XY: 20247 AN XY: 74328

African (AFR) AF: 0.373 AC: 15469 AN: 41428

American (AMR) AF: 0.236 AC: 3605 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1062 AN: 3468

East Asian (EAS) AF: 0.208 AC: 1073 AN: 5160

South Asian (SAS) AF: 0.222 AC: 1070 AN: 4828

European-Finnish (FIN) AF: 0.221 AC: 2340 AN: 10572

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16277 AN: 67978

Other (OTH) AF: 0.257 AC: 541 AN: 2108

Alfa AF: 0.256 Hom.: 9536

Bravo AF: 0.278

Asia WGS AF: 0.236 AC: 817 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.5
DANN	Benign	0.37
PhyloP100		-0.42

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: rs295; hg19: chr8-19816238;