rs559590399

Variant names:

• chr8-19939370-C-G
• rs559590399
• NM_000237.3:c.-71C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-19939370-C-G
• chr8-19939370-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000237.3(LPL):​c.-71C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,488,664 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: LPL NM_000237.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.881
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000886 (135/152316) while in subpopulation AFR AF = 0.00298 (124/41580). AF 95% confidence interval is 0.00255. There are 1 homozygotes in GnomAd4. There are 69 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_000228.1	P06858
	LPL	NM_000237.3	MANE Select	c.-71C>G		5_prime_UTR	Exon 1 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.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000650287.1	MANE Select	c.-71C>G		5_prime_UTR	Exon 1 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 12	ENSP00000635987.1

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152198 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.0000659 AC: 88 AN: 1336348 Hom.: 0 Cov.: 24 AF XY: 0.0000618 AC XY: 41 AN XY: 662928

African (AFR) AF: 0.00199 AC: 61 AN: 30716

American (AMR) AF: 0.000224 AC: 8 AN: 35746

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24746

East Asian (EAS) AF: 0.00 AC: 0 AN: 35950

South Asian (SAS) AF: 0.00 AC: 0 AN: 78250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45178

Middle Eastern (MID) AF: 0.000208 AC: 1 AN: 4804

European-Non Finnish (NFE) AF: 0.00000195 AC: 2 AN: 1025072

Other (OTH) AF: 0.000286 AC: 16 AN: 55886

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152316 Hom.: 1 Cov.: 33 AF XY: 0.000926 AC XY: 69 AN XY: 74474

African (AFR) AF: 0.00298 AC: 124 AN: 41580

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000816

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hyperlipoproteinemia, type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.8
DANN	Benign	0.51
PhyloP100		-0.88
PromoterAI		-0.026	Neutral

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: rs559590399; hg19: chr8-19796881;