8-143215097-G-T

Variant names:

• chr8-143215097-G-T
• rs587777640
• NM_178172.6:c.266G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_178172.6(GPIHBP1):​c.266G>T​(p.Cys89Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.06
• Publications: 15 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a disulfide_bond (size 24) in uniprot entity HDBP1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_178172.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 8-143215097-G-T is Pathogenic according to our data. Variant chr8-143215097-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 144017.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPIHBP1	NM_178172.6	MANE Select	c.266G>T	p.Cys89Phe	missense	Exon 3 of 4	NP_835466.2
	GPIHBP1	NM_001301772.2		c.266G>T	p.Cys89Phe	missense	Exon 3 of 5	NP_001288701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPIHBP1	ENST00000622500.2	TSL:1 MANE Select	c.266G>T	p.Cys89Phe	missense	Exon 3 of 4	ENSP00000480053.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hyperlipoproteinemia, type 1D Pathogenic:1

Oct 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.62	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.90	D
PhyloP100		2.1
PrimateAI	Uncertain	0.49	T
Sift4G	Pathogenic	0.0	D
Vest4		0.91
MutPred		0.94		Loss of sheet (P = 0.0315)
MVP		0.80
ClinPred		0.91	D
GERP RS		3.3
gMVP		0.99
Mutation Taster		=10/90	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777640; hg19: chr8-144296972; COSMIC: COSV100427415;