8-143215486-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_178172.6(GPIHBP1):c.523G>C(p.Gly175Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000732 in 1,609,790 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 3 hom. )

Consequence

GPIHBP1
NM_178172.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:8B:2

Conservation

PhyloP100: -1.76

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01230523).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00196 (299/152310) while in subpopulation AFR AF= 0.00553 (230/41564). AF 95% confidence interval is 0.00495. There are 2 homozygotes in gnomad4. There are 147 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPIHBP1	NM_178172.6 link	c.523G>C	p.Gly175Arg	missense_variant	Exon 4 of 4	ENST00000622500.2	NP_835466.2	Q8IV16
GPIHBP1	NM_001301772.2 link	c.375+148G>C		intron_variant	Intron 4 of 4		NP_001288701.1	Q8IV16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPIHBP1	ENST00000622500.2 link	c.523G>C	p.Gly175Arg	missense_variant	Exon 4 of 4	1	NM_178172.6	ENSP00000480053.1		Q8IV16

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00560

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.000854

AC:

203

AN:

237780

Hom.:

AF XY:

0.000722

AC XY:

AN XY:

130224

show subpopulations

Gnomad AFR exome

AF:

0.00524

Gnomad AMR exome

AF:

0.00162

Gnomad ASJ exome

AF:

0.000413

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000495

Gnomad NFE exome

AF:

0.000525

Gnomad OTH exome

AF:

0.00153

GnomAD4 exome

AF:

0.000603

AC:

879

AN:

1457480

Hom.:

Cov.:

AF XY:

0.000597

AC XY:

433

AN XY:

724970

show subpopulations

Gnomad4 AFR exome

AF:

0.00532

Gnomad4 AMR exome

AF:

0.00169

Gnomad4 ASJ exome

AF:

0.000462

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.000118

Gnomad4 NFE exome

AF:

0.000459

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152310

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00553

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000485

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.00235

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00500

AC:

ESP6500EA

AF:

0.000583

AC:

ExAC

AF:

0.000880

AC:

106

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperlipoproteinemia, type 1D

Pathogenic:3Uncertain:5

Oct 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 02, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2023

New York Genome Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

NM_178172.3:c.523G>C in the GPIHBP1 gene has an allele frequency of 0.005 in African subpopulation in the gnomAD database. The GPIHBP1 c.523G>C (p.Gly175Arg) variant has been detected one individual affected with hyperchylomicronemia in homozygous state (PMID: 21816778). Functional study revealed that G175R variant reduced the expression of GPIHBP1 at the cell surface of CHOpgsA-745 cells (PMID: 21816778). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PM3; PS3; PP4. -

Jun 20, 2019

Hadassah Hebrew University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Uncertain:2Benign:1

May 09, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 34426522, 31589614, 33303402, 21816778, 31785789) -

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_supporting, PS3_supporting -

GPIHBP1-related disorder

Uncertain:1

Nov 14, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GPIHBP1 c.523G>C variant is predicted to result in the amino acid substitution p.Gly175Arg. This variant has been reported in the heterozygous and homozygous states in individuals with pancreatitis, diabetes and hyperchylomicronemia (Charrière et al. 2011. PubMed ID: 21816778; Laurijssen et al. 2022. PubMed ID: 35770288). This variant has also been reported in the heterozygous state in individuals with hypertriglyceridemia, hyperlipidemia and Hyperlipoproteinemia (Chyzhyk et al. 2019. PubMed ID: 30352774; Gill et al. 2020. PubMed ID: 33303402, Table S2; Mor-Shaked et al. 2020. PubMed ID: 33223529). Functional studies showed this variant resulted in reducing the expression of GPIHBP1 at the cell surface; however, the significance of this finding is unclear (Charrière et al. 2011. PubMed ID: 21816778). In ClinVar, this variant has conflicting interpretations of likely benign, uncertain significance, likely pathogenic and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/144016/). This variant is reported in 0.55% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-144297361-G-C). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Benign:1

Dec 06, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.9

DANN

Benign

0.94

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.039

M_CAP

Benign

0.067

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.54

PrimateAI

Benign

0.36

Sift4G

Uncertain

0.015

Vest4

0.18

MVP

0.49

ClinPred

0.039

GERP RS

-4.1

gMVP

0.78

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over