8-143215394-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PS1_Moderate BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.684

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 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	UniProt
GPIHBP1	NM_178172.6	c.431C>T	p.Ser144Phe	missense_variant	4/4	ENST00000622500.2
GPIHBP1	NM_001301772.2	c.375+56C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPIHBP1	ENST00000622500.2	c.431C>T	p.Ser144Phe	missense_variant	4/4	1	NM_178172.6	P1

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6955 AN: 152190 Hom.: 509 Cov.: 34

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

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.: 35 AF XY: 0.00437 AC XY: 3173 AN XY: 726562

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.: 34 AF XY: 0.0433 AC XY: 3227 AN XY: 74482

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.: 87

Bravo AF: 0.0529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.146 AC: 645

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0150 AC: 1821

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2019	This variant is associated with the following publications: (PMID: 32041611, 22239554) -

GPIHBP1-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	19
Dann	Uncertain	0.98
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.041	N
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.031	D
Vest4		0.046
ClinPred		0.021	T
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

Other links and lift over

dbSNP: rs78367243; hg19: chr8-144297269;