8-19965319-G-A

Position:

• chr8-19965319-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000237.3(LPL):​c.*9G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 779,480 control chromosomes in the GnomAD database, including 8,873 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1651 hom., cov: 32)
  • Exomes 𝑓: 0.15 (7222 hom.)
• Consequence: LPL NM_000237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0420

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-19965319-G-A is Benign according to our data. Variant chr8-19965319-G-A is described in ClinVar as [Benign]. Clinvar id is 362417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19965319-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3	c.*9G>A		3_prime_UTR_variant	10/10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.*9G>A		3_prime_UTR_variant	10/10		NM_000237.3	ENSP00000497642	P1
LPL	ENST00000650478.1	c.*260G>A		3_prime_UTR_variant, NMD_transcript_variant	4/4			ENSP00000497560

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21918 AN: 152030 Hom.: 1648 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.236

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.0950

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.158

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.146 AC: 36519 AN: 250584 Hom.: 2801 AF XY: 0.147 AC XY: 19868 AN XY: 135456

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.233

Gnomad EAS exome AF: 0.0951

Gnomad SAS exome AF: 0.132

Gnomad FIN exome AF: 0.156

Gnomad NFE exome AF: 0.153

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.147 AC: 92435 AN: 627332 Hom.: 7222 Cov.: 0 AF XY: 0.148 AC XY: 50474 AN XY: 341746

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.234

Gnomad4 EAS exome AF: 0.0762

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.153

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.144 AC: 21928 AN: 152148 Hom.: 1651 Cov.: 32 AF XY: 0.144 AC XY: 10701 AN XY: 74382

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.156

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.0950

Gnomad4 SAS AF: 0.126

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.158

Gnomad4 OTH AF: 0.145

Alfa AF: 0.153 Hom.: 2188

Bravo AF: 0.143

Asia WGS AF: 0.123 AC: 428 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2017	Variant summary: The LPL c.*9G>A variant causes a missense change involving the alteration of a non-conserved nucleotide. One in silico tool predicts a benign outcome for this variant. The variant of interest has been found in a large, broad control population, ExAC in 17618/121272 control chromosomes at a frequency of 0.1452767, which is approximately 43 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratory classified this variant as likely benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -

Hyperlipoproteinemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Dystrophin deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.2
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4922115; hg19: chr8-19822830;