8-19954456-C-T

Variant names:

• chr8-19954456-C-T
• rs256
• NM_000237.3:c.775+103C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000237.3(LPL):​c.775+103C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,154,498 control chromosomes in the GnomAD database, including 12,207 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1379 hom., cov: 33)
  • Exomes 𝑓: 0.15 (10828 hom.)
• Consequence: LPL NM_000237.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.529
• Publications: 29 publications found

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: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hyperlipidemia, familial combined, LPL related

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-19954456-C-T is Benign according to our data. Variant chr8-19954456-C-T is described in ClinVar as Benign. ClinVar VariationId is 1285932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.211 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LPL	NM_000237.3	c.775+103C>T		intron_variant	Intron 5 of 9	ENST00000650287.1	NP_000228.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LPL	ENST00000650287.1	c.775+103C>T		intron_variant	Intron 5 of 9		NM_000237.3	ENSP00000497642.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18831 AN: 152110 Hom.: 1375 Cov.: 33

Gnomad AFR AF: 0.0621

Gnomad AMI AF: 0.207

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.222

Gnomad SAS AF: 0.183

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.145 AC: 145604 AN: 1002270 Hom.: 10828 AF XY: 0.147 AC XY: 75054 AN XY: 510676

African (AFR) AF: 0.0596 AC: 1410 AN: 23660

American (AMR) AF: 0.146 AC: 5183 AN: 35448

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 3850 AN: 22190

East Asian (EAS) AF: 0.215 AC: 7486 AN: 34888

South Asian (SAS) AF: 0.179 AC: 12706 AN: 70920

European-Finnish (FIN) AF: 0.103 AC: 4966 AN: 48252

Middle Eastern (MID) AF: 0.124 AC: 591 AN: 4778

European-Non Finnish (NFE) AF: 0.144 AC: 103115 AN: 717132

Other (OTH) AF: 0.140 AC: 6297 AN: 45002

GnomAD4 genome AF: 0.124 AC: 18832 AN: 152228 Hom.: 1379 Cov.: 33 AF XY: 0.125 AC XY: 9320 AN XY: 74426

African (AFR) AF: 0.0620 AC: 2575 AN: 41548

American (AMR) AF: 0.153 AC: 2346 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 598 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1141 AN: 5156

South Asian (SAS) AF: 0.183 AC: 883 AN: 4820

European-Finnish (FIN) AF: 0.102 AC: 1082 AN: 10612

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9709 AN: 68020

Other (OTH) AF: 0.128 AC: 271 AN: 2114

Alfa AF: 0.141 Hom.: 3849

Bravo AF: 0.122

Asia WGS AF: 0.197 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.92
DANN	Benign	0.48
PhyloP100		-0.53

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

Other links and lift over

dbSNP: rs256; hg19: chr8-19811967;