chr8-143215294-ACA-CCT

Variant names:

• chr8-143215294-ACA-CCT
• NM_178172.6:c.331_333delACAinsCCT
• GPIHBP1 p.Thr111Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PM1

The NM_178172.6(GPIHBP1):​c.331_333delACAinsCCT​(p.Thr111Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GPIHBP1 NM_178172.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0390
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_178172.6 (GPIHBP1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_178172.6

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.331_333delACAinsCCT	p.Thr111Pro	missense	N/A	NP_835466.2	Q8IV16
	GPIHBP1	NM_001301772.2		c.331_333delACAinsCCT	p.Thr111Pro	missense	N/A	NP_001288701.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPIHBP1	ENST00000622500.2	TSL:1 MANE Select	c.331_333delACAinsCCT	p.Thr111Pro	missense	N/A	ENSP00000480053.1	Q8IV16
	GPIHBP1	ENST00000852007.1		c.376_378delACAinsCCT	p.Thr126Pro	missense	N/A	ENSP00000522066.1
	GPIHBP1	ENST00000852008.1		c.296-4_296-2delACAinsCCT		splice_acceptor splice_region intron	N/A	ENSP00000522067.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.039

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr8-144297169;