NM_000237.3:c.106G>A

Variant names:

• chr8-19948197-G-A
• rs1801177
• NM_000237.3:c.106G>A

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.106G>A​(p.Asp36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,613,866 control chromosomes in the GnomAD database, including 327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. D36D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (61 hom., cov: 31)
  • Exomes 𝑓: 0.016 (266 hom.)
• Consequence: LPL NM_000237.3 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1 B:13 O:3
• Conservation: PhyloP100: 3.48
• Publications: 163 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=0.0077874362).
• BP6: Variant 8-19948197-G-A is Benign according to our data. Variant chr8-19948197-G-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 1552.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 = 0.0222 (3374/152068) while in subpopulation AFR AF = 0.0458 (1900/41482). AF 95% confidence interval is 0.0441. There are 61 homozygotes in GnomAd4. There are 1562 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 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.106G>A	p.Asp36Asn	missense	Exon 2 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.106G>A	p.Asp36Asn	missense	Exon 2 of 10	ENSP00000497642.1	P06858
	LPL	ENST00000965928.1		c.106G>A	p.Asp36Asn	missense	Exon 4 of 12	ENSP00000635987.1
	LPL	ENST00000965929.1		c.106G>A	p.Asp36Asn	missense	Exon 2 of 10	ENSP00000635988.1

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3377 AN: 151950 Hom.: 61 Cov.: 31

Gnomad AFR AF: 0.0459

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0152

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0127

Gnomad FIN AF: 0.00190

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0159

Gnomad OTH AF: 0.0239

GnomAD2 exomes AF: 0.0141 AC: 3554 AN: 251484 AF XY: 0.0146

Gnomad AFR exome AF: 0.0466

Gnomad AMR exome AF: 0.00867

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0160 AC: 23441 AN: 1461798 Hom.: 266 Cov.: 31 AF XY: 0.0160 AC XY: 11635 AN XY: 727214

African (AFR) AF: 0.0489 AC: 1638 AN: 33476

American (AMR) AF: 0.00955 AC: 427 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 163 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0131 AC: 1128 AN: 86250

European-Finnish (FIN) AF: 0.00212 AC: 113 AN: 53420

Middle Eastern (MID) AF: 0.0229 AC: 132 AN: 5768

European-Non Finnish (NFE) AF: 0.0170 AC: 18906 AN: 1111938

Other (OTH) AF: 0.0154 AC: 931 AN: 60386

GnomAD4 genome AF: 0.0222 AC: 3374 AN: 152068 Hom.: 61 Cov.: 31 AF XY: 0.0210 AC XY: 1562 AN XY: 74338

African (AFR) AF: 0.0458 AC: 1900 AN: 41482

American (AMR) AF: 0.0152 AC: 232 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.0123 AC: 59 AN: 4814

European-Finnish (FIN) AF: 0.00190 AC: 20 AN: 10552

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0159 AC: 1083 AN: 67996

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0174 Hom.: 126

Bravo AF: 0.0246

TwinsUK AF: 0.0210 AC: 78

ALSPAC AF: 0.0205 AC: 79

ESP6500AA AF: 0.0454 AC: 200

ESP6500EA AF: 0.0177 AC: 152

ExAC AF: 0.0149 AC: 1811

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0218

ClinVar

ClinVar submissions

Significance: Benign/Likely benign; other

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0078	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.33
Sift	Benign	0.063	T
Sift4G	Uncertain	0.058	T
Polyphen		0.074	B
Vest4		0.055
MPC		0.089
ClinPred		0.022	T
GERP RS		4.3
Varity_R		0.24
gMVP		0.66

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: rs1801177; hg19: chr8-19805708; COSMIC: COSV60931007;