chr8-19939214-T-C

Position:

• chr8-19939214-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000522701.5(LPL):​c.-218-9T>C variant causes a splice polypyrimidine tract, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LPL ENST00000522701.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9398
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 4.07

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3			upstream_gene_variant		ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1			upstream_gene_variant			NM_000237.3	ENSP00000497642	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 437924 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 229754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 29, 2024

Variant summary: LPL c.-227T>C (also reported as "T(-39)C") is located in the untranscribed region upstream of the LPL gene region. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.-227T>C has been reported in the literature in the heterozygous state in at least 1 individual affected with biochemical features consistent with carrier status for Familial Lipoprotein Lipase Deficiency (example, Yang_1995, Yang_1996). These data do not allow any conclusion about variant significance. Post-heparin LPL activity in patient cells was approximately half of normal levels, and in vitro experiments found that this variant disrupts the Oct-1 transcription factor binding site and reduces LPL promoter activity to <15% of controls in a THP-1 monocytic cell line, however the biological impact was not assessed in LPL-relevant cell lines (example, Yang_1995). The following publications have been ascertained in the context of this evaluation (PMID: 9017514, 7753827). ClinVar contains an entry for this variant (Variation ID: 1549). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hyperlipidemia, familial combined, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

May 09, 1995

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Pathogenic	0.79
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-19796725;