8-19953304-C-T

Position:

chr8-19953304-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000237.3(LPL):c.430-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,576,400 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 57 hom. )

Consequence

LPL
NM_000237.3 splice_region, intron

Scores

Splicing: ADA: 0.001226

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.395

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 8-19953304-C-T is Benign according to our data. Variant chr8-19953304-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 362408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19953304-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00459 (699/152204) while in subpopulation AMR AF= 0.034 (520/15288). AF 95% confidence interval is 0.0316. There are 16 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LPL	NM_000237.3 linkuse as main transcript	c.430-6C>T		splice_region_variant, intron_variant		ENST00000650287.1	NP_000228.1	P06858A0A1B1RVA9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1 linkuse as main transcript	c.430-6C>T		splice_region_variant, intron_variant			NM_000237.3	ENSP00000497642.1		P06858
LPL	ENST00000520959.5 linkuse as main transcript	c.202-6C>T		splice_region_variant, intron_variant		4		ENSP00000428496.1		E7EW14

Frequencies

GnomAD3 genomes

AF:

0.00456

AC:

694

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0337

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00827

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00595

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000412

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00789

AC:

1983

AN:

251344

Hom.:

AF XY:

0.00614

AC XY:

834

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.0480

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00386

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.00753

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00221

AC:

3143

AN:

1424196

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

1396

AN XY:

710946

show subpopulations

Gnomad4 AFR exome

AF:

0.000398

Gnomad4 AMR exome

AF:

0.0461

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0101

Gnomad4 SAS exome

AF:

0.000351

Gnomad4 FIN exome

AF:

0.00714

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.00219

GnomAD4 genome

AF:

0.00459

AC:

699

AN:

152204

Hom.:

Cov.:

AF XY:

0.00563

AC XY:

419

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000722

Gnomad4 AMR

AF:

0.0340

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00829

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00595

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00352

Hom.:

Bravo

AF:

0.00628

Asia WGS

AF:

0.00866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2017	Variant summary: The LPL c.430-6C>T variant involves the alteration of a non-conserved intronic nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 731/121160 control chromosomes (15 homozygotes) including ExAC, predominantly observed in the Latino subpopulation at a frequency of 0.051182 (589/11508). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic LPL variant (0.0033541), thus this is likely a benign polymorphism found primarily in the populations of Latino origin. It has also been reported in hypertriglyceridemia patients but without evidence of causality and functional assay indicated that this variant does not affect gene splicing (Nakamura_1996). One clinical diagnostic laboratory (via ClinVar) has classified this variant as likely benign. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	This variant is associated with the following publications: (PMID: 27055971, 9225235) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hyperlipoproteinemia, type I

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

8.8

DANN

Benign

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0012

dbscSNV1_RF

Benign

0.034

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