8-143213859-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178172.6(GPIHBP1):c.90C>G(p.Asp30Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,404,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D30D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.93

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014179558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPIHBP1	NM_178172.6	c.90C>G	p.Asp30Glu	missense_variant	2/4	ENST00000622500.2
GPIHBP1	NM_001301772.2	c.90C>G	p.Asp30Glu	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPIHBP1	ENST00000622500.2	c.90C>G	p.Asp30Glu	missense_variant	2/4	1	NM_178172.6	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD3 exomes AF: 0.00000618 AC: 1 AN: 161864 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 85522

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000396

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 4 AN: 1404678 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 2 AN XY: 693516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ExAC AF: 0.00000877 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with GPIHBP1-related conditions. This variant is present in population databases (rs776835638, gnomAD 0.004%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 30 of the GPIHBP1 protein (p.Asp30Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.021
Dann	Benign	0.42
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.0050	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
Sift4G	Benign	0.34	T
Vest4		0.13
MutPred		0.16		Loss of loop (P = 0.0235);
MVP		0.25
ClinPred		0.10	T
GERP RS		-5.4
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776835638; hg19: chr8-144295734;