chr8-19966534-C-A

Variant names:

• chr8-19966534-C-A
• rs3735964
• NM_000237.3:c.*1224C>A

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.*1224C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 152,154 control chromosomes in the GnomAD database, including 641 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (641 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: LPL NM_000237.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.136

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=-0.66).
• BP6: Variant 8-19966534-C-A is Benign according to our data. Variant chr8-19966534-C-A is described in ClinVar as [Benign]. Clinvar id is 362440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.*1224C>A		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.*1224C>A		3_prime_UTR_variant	Exon 10 of 10		NM_000237.3	ENSP00000497642.1
LPL	ENST00000650478.1	n.*1475C>A		non_coding_transcript_exon_variant	Exon 4 of 4			ENSP00000497560.1
LPL	ENST00000650478.1	n.*1475C>A		3_prime_UTR_variant	Exon 4 of 4			ENSP00000497560.1

Frequencies

GnomAD3 genomes AF: 0.0921 AC: 14003 AN: 152036 Hom.: 642 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.0833

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0966

Gnomad FIN AF: 0.0923

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0927

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0920 AC: 13993 AN: 152154 Hom.: 641 Cov.: 32 AF XY: 0.0912 AC XY: 6788 AN XY: 74392

Gnomad4 AFR AF: 0.0640

Gnomad4 AMR AF: 0.0832

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0963

Gnomad4 FIN AF: 0.0923

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0918

Alfa AF: 0.0988 Hom.: 335

Bravo AF: 0.0893

Asia WGS AF: 0.100 AC: 347 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 03, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25814643) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.66
CADD	Benign	12
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs3735964; hg19: chr8-19824045;