rs268

Variant names:

• chr8-19956018-A-G
• rs268
• NM_000237.3:c.953A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 7P and 13B. PS3 PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000237.3(LPL):​c.953A>G​(p.Asn318Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,614,214 control chromosomes in the GnomAD database, including 243 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001142388: Functional analyses reveal that Asn291Ser mutation in the LPL gene is associated with significantly reduced HDL levels and results in a significant decrease in LPL catalytic activity. PMID:8541837".

• Frequency:
  • Genomes: 𝑓 0.013 (14 hom., cov: 32)
  • Exomes 𝑓: 0.016 (229 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:11 B:7 O:1
• Conservation: PhyloP100: 2.93
• Publications: 296 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001142388: Functional analyses reveal that Asn291Ser mutation in the LPL gene is associated with significantly reduced HDL levels and results in a significant decrease in LPL catalytic activity. PMID: 8541837
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000237.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Trascript score misZ: -0.36753 (below the threshold of 3.09). GenCC associations: The gene is linked to familial lipoprotein lipase deficiency, hyperlipidemia, familial combined, LPL related.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009144157).
• BP6: Variant 8-19956018-A-G is Benign according to our data. Variant chr8-19956018-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1550.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0127 (1936/152336) while in subpopulation NFE AF = 0.0186 (1264/68028). AF 95% confidence interval is 0.0177. There are 14 homozygotes in GnomAd4. There are 968 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.953A>G	p.Asn318Ser	missense	Exon 6 of 10	NP_000228.1	P06858

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LPL	ENST00000650287.1	MANE Select	c.953A>G	p.Asn318Ser	missense	Exon 6 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.953A>G	p.Asn318Ser	missense	Exon 8 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.950A>G	p.Asn317Ser	missense	Exon 6 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152218 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0163

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.0225

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.0128 AC: 3212 AN: 251336 AF XY: 0.0124

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.00674

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0207

Gnomad NFE exome AF: 0.0197

Gnomad OTH exome AF: 0.0127

GnomAD4 exome AF: 0.0160 AC: 23443 AN: 1461878 Hom.: 229 Cov.: 32 AF XY: 0.0157 AC XY: 11445 AN XY: 727246

African (AFR) AF: 0.00269 AC: 90 AN: 33478

American (AMR) AF: 0.00671 AC: 300 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0108 AC: 281 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00243 AC: 210 AN: 86258

European-Finnish (FIN) AF: 0.0206 AC: 1103 AN: 53416

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5768

European-Non Finnish (NFE) AF: 0.0186 AC: 20633 AN: 1112002

Other (OTH) AF: 0.0133 AC: 803 AN: 60396

GnomAD4 genome AF: 0.0127 AC: 1936 AN: 152336 Hom.: 14 Cov.: 32 AF XY: 0.0130 AC XY: 968 AN XY: 74492

African (AFR) AF: 0.00284 AC: 118 AN: 41574

American (AMR) AF: 0.0163 AC: 249 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4832

European-Finnish (FIN) AF: 0.0225 AC: 239 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1264 AN: 68028

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.0159 Hom.: 74

Bravo AF: 0.0110

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0187 AC: 72

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0184 AC: 158

ExAC AF: 0.0134 AC: 1622

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0170

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Hyperlipoproteinemia, type I (5)
1	2	2	not provided (5)
1	3	-	Hyperlipidemia, familial combined, LPL related (4)
-	-	3	not specified (3)
-	1	1	Cardiovascular phenotype (2)
-	1	-	Hyperlipidemia, familial combined, LPL related;C0023817:Hyperlipoproteinemia, type I (1)
-	-	-	Hyperlipidemia, familial combined, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.011
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.31
Sift	Benign	0.25	T
Sift4G	Benign	0.17	T
Polyphen		0.10	B
Vest4		0.049
MPC		0.066
ClinPred		0.033	T
GERP RS		6.1
Varity_R		0.29
gMVP		0.68

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: rs268; hg19: chr8-19813529; COSMIC: COSV99073672; COSMIC: COSV99073672;