8-19965299-C-T

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.*-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0987 in 780,010 control chromosomes in the GnomAD database, including 4,054 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (660 hom., cov: 32)
  • Exomes 𝑓: 0.10 (3394 hom.)
• Consequence: LPL NM_000237.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00003292
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.151

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=-0.75).
• BP6: Variant 8-19965299-C-T is Benign according to our data. Variant chr8-19965299-C-T is described in ClinVar as [Benign]. Clinvar id is 1269038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-19965299-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LPL	NM_000237.3	c.*-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000650287.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LPL	ENST00000650287.1	c.*-11C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_000237.3	P1
LPL	ENST00000650478.1	c.*251-11C>T		splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0942 AC: 14328 AN: 152036 Hom.: 661 Cov.: 32

Gnomad AFR AF: 0.0716

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0836

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0921

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0934

GnomAD3 exomes AF: 0.0954 AC: 23944 AN: 250918 Hom.: 1282 AF XY: 0.0971 AC XY: 13163 AN XY: 135630

Gnomad AFR exome AF: 0.0721

Gnomad AMR exome AF: 0.0583

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.112

Gnomad SAS exome AF: 0.0961

Gnomad FIN exome AF: 0.0893

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0998

GnomAD4 exome AF: 0.0999 AC: 62700 AN: 627856 Hom.: 3394 Cov.: 0 AF XY: 0.101 AC XY: 34510 AN XY: 342038

Gnomad4 AFR exome AF: 0.0714

Gnomad4 AMR exome AF: 0.0611

Gnomad4 ASJ exome AF: 0.110

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0938

Gnomad4 FIN exome AF: 0.0905

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.0950

GnomAD4 genome AF: 0.0941 AC: 14316 AN: 152154 Hom.: 660 Cov.: 32 AF XY: 0.0933 AC XY: 6937 AN XY: 74376

Gnomad4 AFR AF: 0.0714

Gnomad4 AMR AF: 0.0836

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0964

Gnomad4 FIN AF: 0.0921

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0924

Alfa AF: 0.0955 Hom.: 145

Bravo AF: 0.0920

Asia WGS AF: 0.106 AC: 367 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	4.3
Dann	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000033
dbscSNV1_RF	Benign	0.0
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: rs11570891; hg19: chr8-19822810; COSMIC: COSV60931023;