ENST00000965928.1:c.-153-130G>T

Variant names:

• chr8-19939158-G-T
• rs80351041
• ENST00000965928.1:c.-153-130G>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The ENST00000965928.1(LPL):​c.-153-130G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00731 in 512,914 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0067 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (15 hom.)
• Consequence: LPL ENST00000965928.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.24
• Publications: 5 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 8-19939158-G-T is Benign according to our data. Variant chr8-19939158-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362398.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00666 (1013/152180) while in subpopulation NFE AF = 0.0113 (766/68008). AF 95% confidence interval is 0.0106. There are 9 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000965928.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.-283G>T		upstream_gene	N/A	NP_000228.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000965928.1		c.-153-130G>T		intron	N/A	ENSP00000635987.1
	LPL	ENST00000524029.5	TSL:4	c.-153-130G>T		intron	N/A	ENSP00000428237.1
	LPL	ENST00000520959.5	TSL:4	c.-140-9022G>T		intron	N/A	ENSP00000428496.1

Frequencies

GnomAD3 genomes AF: 0.00667 AC: 1014 AN: 152062 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0113

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.00758 AC: 2735 AN: 360734 Hom.: 15 Cov.: 0 AF XY: 0.00741 AC XY: 1396 AN XY: 188330

African (AFR) AF: 0.00268 AC: 27 AN: 10090

American (AMR) AF: 0.00315 AC: 43 AN: 13654

Ashkenazi Jewish (ASJ) AF: 0.00182 AC: 21 AN: 11514

East Asian (EAS) AF: 0.00 AC: 0 AN: 23856

South Asian (SAS) AF: 0.00272 AC: 102 AN: 37502

European-Finnish (FIN) AF: 0.00681 AC: 159 AN: 23356

Middle Eastern (MID) AF: 0.00248 AC: 4 AN: 1616

European-Non Finnish (NFE) AF: 0.0103 AC: 2235 AN: 217564

Other (OTH) AF: 0.00667 AC: 144 AN: 21582

GnomAD4 genome AF: 0.00666 AC: 1013 AN: 152180 Hom.: 9 Cov.: 32 AF XY: 0.00659 AC XY: 490 AN XY: 74378

African (AFR) AF: 0.00181 AC: 75 AN: 41532

American (AMR) AF: 0.00320 AC: 49 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5158

South Asian (SAS) AF: 0.00374 AC: 18 AN: 4808

European-Finnish (FIN) AF: 0.00538 AC: 57 AN: 10592

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0113 AC: 766 AN: 68008

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00768 Hom.: 2

Bravo AF: 0.00593

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hyperlipoproteinemia, type I (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.94
PhyloP100		3.2
PromoterAI		-0.20	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: rs80351041; hg19: chr8-19796669;