chr8-143215394-C-T

Variant names:

• chr8-143215394-C-T
• rs78367243
• NM_178172.6:c.431C>T

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.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. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:6
• Conservation: PhyloP100: 0.684
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• 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 VariationId is 1266579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

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.431C>T	p.Ser144Phe	missense	Exon 4 of 4	NP_835466.2	Q8IV16
	GPIHBP1	NM_001301772.2		c.375+56C>T		intron	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.431C>T	p.Ser144Phe	missense	Exon 4 of 4	ENSP00000480053.1	Q8IV16
	GPIHBP1	ENST00000852007.1		c.476C>T	p.Ser159Phe	missense	Exon 5 of 5	ENSP00000522066.1
	GPIHBP1	ENST00000852008.1		c.392C>T	p.Ser131Phe	missense	Exon 4 of 4	ENSP00000522067.1

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

GnomAD2 exomes AF: 0.0127 AC: 3158 AN: 249206 AF XY: 0.00938

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 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

African (AFR) AF: 0.162 AC: 5421 AN: 33480

American (AMR) AF: 0.0109 AC: 487 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 318 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000301 AC: 26 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52156

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000442 AC: 491 AN: 1111972

Other (OTH) AF: 0.0103 AC: 620 AN: 60380

GnomAD4 genome AF: 0.0457 AC: 6959 AN: 152306 Hom.: 508 Cov.: 34 AF XY: 0.0433 AC XY: 3227 AN XY: 74482

African (AFR) AF: 0.158 AC: 6565 AN: 41530

American (AMR) AF: 0.0170 AC: 260 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68028

Other (OTH) AF: 0.0298 AC: 63 AN: 2116

Alfa AF: 0.0218 Hom.: 385

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GPIHBP1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.68
PrimateAI	Benign	0.33	T
Sift4G	Uncertain	0.031	D
Vest4		0.046
ClinPred		0.021	T
GERP RS		2.7
gMVP		0.74
Mutation Taster		=97/3	polymorphism (auto)

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: rs78367243; hg19: chr8-144297269;