rs1059611

Variant names:

• chr8-19967052-T-C
• rs1059611
• NM_000237.3:c.*1742T>C

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.*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
• Publications: 56 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=-0.85).
• BP6: Variant 8-19967052-T-C is Benign according to our data. Variant chr8-19967052-T-C is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.*1742T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.*1742T>C		3_prime_UTR_variant	Exon 10 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.*1993T>C		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497560.1
LPL	ENST00000650478.1	n.*1993T>C		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497560.1

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

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: 0.0888 AC: 38 AN: 428

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 4

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

African (AFR) AF: 0.183 AC: 7586 AN: 41486

American (AMR) AF: 0.0941 AC: 1437 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 490 AN: 3470

East Asian (EAS) AF: 0.109 AC: 563 AN: 5176

South Asian (SAS) AF: 0.101 AC: 486 AN: 4822

European-Finnish (FIN) AF: 0.0920 AC: 976 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.109 AC: 7383 AN: 68002

Other (OTH) AF: 0.120 AC: 252 AN: 2106

Alfa AF: 0.118 Hom.: 3212

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperlipoproteinemia, type I Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.14

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: rs1059611; hg19: chr8-19824563;