rs11538389

Variant names:

• chr8-143213308-T-G
• rs11538389
• NM_178172.6:c.41T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178172.6(GPIHBP1):​c.41T>G​(p.Phe14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.895 in 1,595,946 control chromosomes in the GnomAD database, including 640,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. F14F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.89 (60546 hom., cov: 32)
  • Exomes 𝑓: 0.90 (580428 hom.)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.176
• Publications: 31 publications found

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: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046406984).
• BP6: Variant 8-143213308-T-G is Benign according to our data. Variant chr8-143213308-T-G is described in ClinVar as Benign. ClinVar VariationId is 769221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPIHBP1	NM_178172.6	c.41T>G	p.Phe14Cys	missense_variant	Exon 1 of 4	ENST00000622500.2	NP_835466.2
GPIHBP1	NM_001301772.2	c.41T>G	p.Phe14Cys	missense_variant	Exon 1 of 5		NP_001288701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPIHBP1	ENST00000622500.2	c.41T>G	p.Phe14Cys	missense_variant	Exon 1 of 4	1	NM_178172.6	ENSP00000480053.1

Frequencies

GnomAD3 genomes AF: 0.891 AC: 135494 AN: 152060 Hom.: 60501 Cov.: 32

Gnomad AFR AF: 0.891

Gnomad AMI AF: 0.971

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.706

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.883

Gnomad MID AF: 0.918

Gnomad NFE AF: 0.912

Gnomad OTH AF: 0.898

GnomAD4 exome AF: 0.896 AC: 1292910 AN: 1443768 Hom.: 580428 Cov.: 47 AF XY: 0.894 AC XY: 641095 AN XY: 717260

African (AFR) AF: 0.894 AC: 29910 AN: 33438

American (AMR) AF: 0.859 AC: 36194 AN: 42132

Ashkenazi Jewish (ASJ) AF: 0.936 AC: 24109 AN: 25754

East Asian (EAS) AF: 0.684 AC: 26796 AN: 39174

South Asian (SAS) AF: 0.829 AC: 69262 AN: 83542

European-Finnish (FIN) AF: 0.884 AC: 40777 AN: 46128

Middle Eastern (MID) AF: 0.929 AC: 5336 AN: 5746

European-Non Finnish (NFE) AF: 0.909 AC: 1007266 AN: 1107918

Other (OTH) AF: 0.889 AC: 53260 AN: 59936

GnomAD4 genome AF: 0.891 AC: 135594 AN: 152178 Hom.: 60546 Cov.: 32 AF XY: 0.885 AC XY: 65834 AN XY: 74388

African (AFR) AF: 0.891 AC: 36979 AN: 41518

American (AMR) AF: 0.872 AC: 13338 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3254 AN: 3472

East Asian (EAS) AF: 0.706 AC: 3631 AN: 5146

South Asian (SAS) AF: 0.822 AC: 3961 AN: 4820

European-Finnish (FIN) AF: 0.883 AC: 9362 AN: 10606

Middle Eastern (MID) AF: 0.918 AC: 270 AN: 294

European-Non Finnish (NFE) AF: 0.912 AC: 62028 AN: 68006

Other (OTH) AF: 0.893 AC: 1887 AN: 2114

Alfa AF: 0.904 Hom.: 104741

Bravo AF: 0.892

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.1
MetaRNN	Benign	0.0046	T
PhyloP100		0.18
Sift4G	Benign	1.0	T
Vest4		0.24
PromoterAI		-0.022	Neutral
gMVP		0.66

Splicing

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

Other links and lift over

dbSNP: rs11538389; hg19: chr8-144295183;