Genetic Variant LPL:c.-172_-171dupCC (chr8-19939265-T-TCC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000237.3(LPL):c.-172_-171dupCC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00245 in 616,782 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0071 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 6 hom. )

Consequence

LPL
NM_000237.3 5_prime_UTR

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -0.0180

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

familial lipoprotein lipase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics
hyperlipidemia, familial combined, LPL related
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

LPL links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 8-19939265-T-TCC is Benign according to our data. Variant chr8-19939265-T-TCC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 362400.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00714 (1087/152202) while in subpopulation AFR AF = 0.0251 (1044/41518). AF 95% confidence interval is 0.0239. There are 10 homozygotes in GnomAd4. There are 490 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 10 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	NM_000237.3	MANE Select	c.-172_-171dupCC		5_prime_UTR	Exon 1 of 10	NP_000228.1	P06858

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
LPL	ENST00000650287.1	MANE Select	c.-172_-171dupCC	5_prime_UTR	Exon 1 of 10	ENSP00000497642.1	P06858
LPL	ENST00000965929.1		c.-172_-171dupCC	5_prime_UTR	Exon 1 of 10	ENSP00000635988.1
LPL	ENST00000965931.1		c.-172_-171dupCC	5_prime_UTR	Exon 1 of 10	ENSP00000635990.1

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1084

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00223

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00239

GnomAD4 exome

AF:

0.000908

AC:

422

AN:

464580

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

177

AN XY:

245556

show subpopulations

African (AFR)

AF:

0.0247

AC:

322

AN:

13042

American (AMR)

AF:

0.00157

AC:

AN:

21644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14302

East Asian (EAS)

AF:

0.00

AC:

AN:

31134

South Asian (SAS)

AF:

0.0000837

AC:

AN:

47794

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30626

Middle Eastern (MID)

AF:

0.00149

AC:

AN:

2018

European-Non Finnish (NFE)

AF:

0.0000397

AC:

AN:

277264

Other (OTH)

AF:

0.00179

AC:

AN:

26756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00714

AC:

1087

AN:

152202

Hom.:

Cov.:

AF XY:

0.00659

AC XY:

490

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.0251

AC:

1044

AN:

41518

American (AMR)

AF:

0.00222

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68004

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

111

166

222

277

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00527

Hom.:

Bravo

AF:

0.00806

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Hyperlipoproteinemia, type I (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.018

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over