8-143215394-C-T

Position:

chr8-143215394-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_ModerateBP4_StrongBP6_Very_StrongBA1

The NM_178172.6(GPIHBP1):c.431C>T(p.Ser144Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0089 in 1,612,860 control chromosomes in the GnomAD database, including 972 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: 𝑓 0.046 ( 508 hom., cov: 34)

Exomes 𝑓: 0.0051 ( 464 hom. )

Consequence

GPIHBP1
NM_178172.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.684

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 -18 ACMG points.

PS1

Transcript NM_178172.6 (GPIHBP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

BP4

Computational evidence support a benign effect (MetaRNN=0.0016706288).

BP6

Variant 8-143215394-C-T is Benign according to our data. Variant chr8-143215394-C-T is described in ClinVar as [Benign]. Clinvar id is 1266579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143215394-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPIHBP1	NM_178172.6 linkuse as main transcript	c.431C>T	p.Ser144Phe	missense_variant	4/4	ENST00000622500.2	NP_835466.2	Q8IV16
GPIHBP1	NM_001301772.2 linkuse as main transcript	c.375+56C>T		intron_variant			NP_001288701.1	Q8IV16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPIHBP1	ENST00000622500.2 linkuse as main transcript	c.431C>T	p.Ser144Phe	missense_variant	4/4	1	NM_178172.6	ENSP00000480053.1		Q8IV16

Frequencies

GnomAD3 genomes

AF:

0.0457

AC:

6955

AN:

152190

Hom.:

509

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0171

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0127

AC:

3158

AN:

249206

Hom.:

214

AF XY:

0.00938

AC XY:

1269

AN XY:

135262

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.00941

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000519

Gnomad OTH exome

AF:

0.00903

GnomAD4 exome

AF:

0.00506

AC:

7396

AN:

1460554

Hom.:

464

Cov.:

AF XY:

0.00437

AC XY:

3173

AN XY:

726562

show subpopulations

Gnomad4 AFR exome

AF:

0.162

Gnomad4 AMR exome

AF:

0.0109

Gnomad4 ASJ exome

AF:

0.0122

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000442

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.0457

AC:

6959

AN:

152306

Hom.:

508

Cov.:

AF XY:

0.0433

AC XY:

3227

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.158

Gnomad4 AMR

AF:

0.0170

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.00915

Hom.:

Bravo

AF:

0.0529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.146

AC:

645

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.0150

AC:

1821

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2019	This variant is associated with the following publications: (PMID: 32041611, 22239554) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

GPIHBP1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2019

This alteration is classified as 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

Benign

0.23

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.041

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.93

PrimateAI

Benign

0.33

Sift4G

Uncertain

0.031

Vest4

0.046

ClinPred

0.021

GERP RS

2.7

gMVP

0.74

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