rs300

Variant names:

• chr8-19959376-A-G
• rs300
• NM_000237.3:c.1135A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000237.3(LPL):​c.1135A>G​(p.Thr379Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,878 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T379I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.29
• Publications: 11 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: Benign. The variant received -19 ACMG points.

• 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=0.008776933).
• BP6: Variant 8-19959376-A-G is Benign according to our data. Variant chr8-19959376-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 495741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00324 (493/152106) while in subpopulation AFR AF = 0.0108 (449/41470). AF 95% confidence interval is 0.01. There are 1 homozygotes in GnomAd4. There are 220 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.1135A>G	p.Thr379Ala	missense	Exon 7 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.1135A>G	p.Thr379Ala	missense	Exon 7 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.1135A>G	p.Thr379Ala	missense	Exon 9 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.1132A>G	p.Thr378Ala	missense	Exon 7 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 494 AN: 151988 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.000800 AC: 201 AN: 251160 AF XY: 0.000508

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000314 AC: 459 AN: 1461772 Hom.: 3 Cov.: 32 AF XY: 0.000249 AC XY: 181 AN XY: 727178

African (AFR) AF: 0.0114 AC: 381 AN: 33478

American (AMR) AF: 0.000671 AC: 30 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111970

Other (OTH) AF: 0.000596 AC: 36 AN: 60388

GnomAD4 genome AF: 0.00324 AC: 493 AN: 152106 Hom.: 1 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74358

African (AFR) AF: 0.0108 AC: 449 AN: 41470

American (AMR) AF: 0.00196 AC: 30 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67986

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.000901 Hom.: 4

Bravo AF: 0.00393

ESP6500AA AF: 0.0129 AC: 57

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00108 AC: 131

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Hyperlipoproteinemia, type I (2)
-	-	2	not specified (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	LPL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.0076
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.20
Sift	Benign	0.062	T
Sift4G	Benign	0.16	T
Polyphen		0.24	B
Vest4		0.31
MVP		0.86
MPC		0.13
ClinPred		0.026	T
GERP RS		4.6
Varity_R		0.14
gMVP		0.64

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: rs300; hg19: chr8-19816887;