NM_178172.6:c.523G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G175S) has been classified as Likely benign.

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:9B:2

Conservation

PhyloP100: -1.76

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

hyperlipoproteinemia, type 1D
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

GPIHBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178172.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPIHBP1	NM_178172.6	MANE Select	c.523G>C	p.Gly175Arg	missense	Exon 4 of 4	NP_835466.2	Q8IV16
	GPIHBP1	NM_001301772.2		c.375+148G>C		intron	N/A	NP_001288701.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPIHBP1	ENST00000622500.2	TSL:1 MANE Select	c.523G>C	p.Gly175Arg	missense	Exon 4 of 4	ENSP00000480053.1	Q8IV16
GPIHBP1	ENST00000852007.1		c.568G>C	p.Gly190Arg	missense	Exon 5 of 5	ENSP00000522066.1
GPIHBP1	ENST00000852008.1		c.484G>C	p.Gly162Arg	missense	Exon 4 of 4	ENSP00000522067.1

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

GnomAD2 exomes

AF:

0.000854

AC:

203

AN:

237780

AF XY:

0.000722

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 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

African (AFR)

AF:

0.00532

AC:

178

AN:

33442

American (AMR)

AF:

0.00169

AC:

AN:

44482

Ashkenazi Jewish (ASJ)

AF:

0.000462

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39638

South Asian (SAS)

AF:

0.0000581

AC:

AN:

86002

European-Finnish (FIN)

AF:

0.000118

AC:

AN:

50950

Middle Eastern (MID)

AF:

0.00197

AC:

AN:

5570

European-Non Finnish (NFE)

AF:

0.000459

AC:

510

AN:

1111154

Other (OTH)

AF:

0.00136

AC:

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00196

AC:

299

AN:

152310

Hom.:

Cov.:

AF XY:

0.00197

AC XY:

147

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00553

AC:

230

AN:

41564

American (AMR)

AF:

0.00124

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68018

Other (OTH)

AF:

0.00426

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperlipoproteinemia, type 1D (8)

not provided (3)

Cardiovascular phenotype (2)

GPIHBP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

6.9

(source)

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

PhyloP100

-1.8

PrimateAI

Benign

0.36

Sift4G

Uncertain

0.015

Vest4

0.18

MVP

0.49

ClinPred

0.039

GERP RS

-4.1

gMVP

0.78

Mutation Taster

=36/64

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over