rs1059611

Positions:

• chr8-19967052-T-C

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.*1742T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 152,586 control chromosomes in the GnomAD database, including 1,338 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1337 hom., cov: 32)
  • Exomes 𝑓: 0.087 (1 hom.)
• Consequence: LPL NM_000237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.142

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=-0.85).
• BP6: Variant 8-19967052-T-C is Benign according to our data. Variant chr8-19967052-T-C is described in ClinVar as [Benign]. Clinvar id is 362448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3	c.*1742T>C		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.*1742T>C		3_prime_UTR_variant	10/10		NM_000237.3	ENSP00000497642	P1
LPL	ENST00000650478.1	c.*1993T>C		3_prime_UTR_variant, NMD_transcript_variant	4/4			ENSP00000497560

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19346 AN: 152032 Hom.: 1337 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0941

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0920

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.109

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.0872 AC: 38 AN: 436 Hom.: 1 Cov.: 0 AF XY: 0.0871 AC XY: 23 AN XY: 264

Gnomad4 FIN exome AF: 0.0888

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.127 AC: 19346 AN: 152150 Hom.: 1337 Cov.: 32 AF XY: 0.125 AC XY: 9263 AN XY: 74392

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0941

Gnomad4 ASJ AF: 0.141

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0920

Gnomad4 NFE AF: 0.109

Gnomad4 OTH AF: 0.120

Alfa AF: 0.117 Hom.: 1123

Bravo AF: 0.129

Asia WGS AF: 0.109 AC: 379 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hyperlipoproteinemia, type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.83
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1059611; hg19: chr8-19824563;