Genetic Variant LPL:c.*1846C>T (chr8-19967156-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000237.3(LPL):c.*1846C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.35 in 152,408 control chromosomes in the GnomAD database, including 10,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 10194 hom., cov: 32)

Exomes 𝑓: 0.28 ( 21 hom. )

Consequence

LPL
NM_000237.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.585

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 8-19967156-C-T is Benign according to our data. Variant chr8-19967156-C-T is described in ClinVar as [Benign]. Clinvar id is 362452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3 link	c.*1846C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LPL	ENST00000650287.1 link	c.*1846C>T	3_prime_UTR_variant	Exon 10 of 10	NM_000237.3	ENSP00000497642.1	P06858
LPL	ENST00000650478.1 link	n.*2097C>T	non_coding_transcript_exon_variant	Exon 4 of 4		ENSP00000497560.1	A0A3B3IT60
LPL	ENST00000650478.1 link	n.*2097C>T	3_prime_UTR_variant	Exon 4 of 4		ENSP00000497560.1	A0A3B3IT60

Frequencies

GnomAD3 genomes

AF:

0.350

AC:

53153

AN:

151858

Hom.:

10179

Cov.:

show subpopulations

Gnomad AFR

AF:

0.511

Gnomad AMI

AF:

0.439

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.436

Gnomad EAS

AF:

0.203

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.292

Gnomad OTH

AF:

0.334

GnomAD4 exome

AF:

0.275

AC:

119

AN:

432

Hom.:

Cov.:

AF XY:

0.254

AC XY:

AN XY:

260

show subpopulations

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.500

GnomAD4 genome

AF:

0.350

AC:

53212

AN:

151976

Hom.:

10194

Cov.:

AF XY:

0.345

AC XY:

25638

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.511

Gnomad4 AMR

AF:

0.298

Gnomad4 ASJ

AF:

0.436

Gnomad4 EAS

AF:

0.203

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.258

Gnomad4 NFE

AF:

0.292

Gnomad4 OTH

AF:

0.334

Alfa

AF:

0.306

Hom.:

8954

Bravo

AF:

0.360

Asia WGS

AF:

0.256

AC:

889

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperlipoproteinemia, type I

Benign:1

Jan 13, 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

-0.89

CADD

Benign

1.3

DANN

Benign

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over