8-143215394-C-G

Variant names:

• chr8-143215394-C-G
• rs78367243
• NM_178172.6:c.431C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178172.6(GPIHBP1):​c.431C>G​(p.Ser144Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S144F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.684
• Publications: 10 publications found

Genes affected

GPIHBP1 (HGNC:24945): (glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1) This gene encodes a capillary endothelial cell protein that facilitates the lipolytic processing of triglyceride-rich lipoproteins. The encoded protein is a glycosylphosphatidylinositol-anchored protein that is a member of the lymphocyte antigen 6 (Ly6) family. This protein plays a major role in transporting lipoprotein lipase (LPL) from the subendothelial spaces to the capillary lumen. Mutations in this gene are the cause of hyperlipoproteinemia, type 1D. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

GPIHBP1 Gene-Disease associations (from GenCC):

• hyperlipoproteinemia, type 1D

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22188348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPIHBP1	NM_178172.6	c.431C>G	p.Ser144Cys	missense_variant	Exon 4 of 4	ENST00000622500.2	NP_835466.2
GPIHBP1	NM_001301772.2	c.375+56C>G		intron_variant	Intron 4 of 4		NP_001288701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPIHBP1	ENST00000622500.2	c.431C>G	p.Ser144Cys	missense_variant	Exon 4 of 4	1	NM_178172.6	ENSP00000480053.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 385

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.96
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.069	N
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.50	T
PhyloP100		0.68
PrimateAI	Benign	0.34	T
Sift4G	Uncertain	0.052	T
Vest4		0.098
MutPred		0.31		Loss of glycosylation at S144 (P = 0.0479);
MVP		0.69
ClinPred		0.48	T
GERP RS		2.7
gMVP		0.74
Mutation Taster		=95/5	polymorphism

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: rs78367243; hg19: chr8-144297269;