8-19967357-G-A

Variant names:

• chr8-19967357-G-A
• rs3916027
• NM_000237.3:c.*2047G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000237.3(LPL):​c.*2047G>A variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.303 in 152,084 control chromosomes in the GnomAD database, including 7,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7351 hom., cov: 33)
  • Exomes 𝑓: 0.23 (2 hom.)
• Consequence: LPL NM_000237.3 downstream_gene
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0550
• Publications: 23 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 8-19967357-G-A is Benign according to our data. Variant chr8-19967357-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.*2047G>A		downstream_gene	N/A	NP_000228.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.*2047G>A		downstream_gene	N/A	ENSP00000497642.1
	LPL	ENST00000650478.1		n.*2298G>A		downstream_gene	N/A	ENSP00000497560.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46008 AN: 151902 Hom.: 7340 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.248

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.234 AC: 15 AN: 64 Hom.: 2 AF XY: 0.229 AC XY: 11 AN XY: 48

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.226 AC: 14 AN: 62

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.303 AC: 46042 AN: 152020 Hom.: 7351 Cov.: 33 AF XY: 0.300 AC XY: 22276 AN XY: 74302

African (AFR) AF: 0.404 AC: 16724 AN: 41416

American (AMR) AF: 0.262 AC: 3997 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1285 AN: 3466

East Asian (EAS) AF: 0.205 AC: 1058 AN: 5162

South Asian (SAS) AF: 0.231 AC: 1111 AN: 4812

European-Finnish (FIN) AF: 0.248 AC: 2627 AN: 10580

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18189 AN: 67980

Other (OTH) AF: 0.291 AC: 615 AN: 2116

Alfa AF: 0.336 Hom.: 2500

Bravo AF: 0.308

Asia WGS AF: 0.242 AC: 839 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.1
DANN	Benign	0.54
PhyloP100		0.055

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3916027; hg19: chr8-19824868;