19-35065840-T-C

Position:

• chr19-35065840-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384133.1(HPN):​c.1051-28T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.915 in 1,612,326 control chromosomes in the GnomAD database, including 677,427 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.89 (60256 hom., cov: 33)
  • Exomes 𝑓: 0.92 (617171 hom.)
• Consequence: HPN NM_001384133.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600

Genes affected

HPN (HGNC:5155): (hepsin) This gene encodes a type II transmembrane serine protease that may be involved in diverse cellular functions, including blood coagulation and the maintenance of cell morphology. Expression of the encoded protein is associated with the growth and progression of cancers, particularly prostate cancer. The protein is cleaved into a catalytic serine protease chain and a non-catalytic scavenger receptor cysteine-rich chain, which associate via a single disulfide bond. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

HPN-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: This place is a probable branch point but rather VUS (scored 5 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HPN	NM_001384133.1	c.1051-28T>C		intron_variant		ENST00000672452.2	NP_001371062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HPN	ENST00000672452.2	c.1051-28T>C		intron_variant			NM_001384133.1	ENSP00000500664.1

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134852 AN: 152082 Hom.: 60226 Cov.: 33

Gnomad AFR AF: 0.793

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.965

Gnomad EAS AF: 0.844

Gnomad SAS AF: 0.705

Gnomad FIN AF: 0.937

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.905

GnomAD3 exomes AF: 0.899 AC: 224756 AN: 250030 Hom.: 101861 AF XY: 0.892 AC XY: 120629 AN XY: 135284

Gnomad AFR exome AF: 0.796

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.964

Gnomad EAS exome AF: 0.851

Gnomad SAS exome AF: 0.718

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.938

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.918 AC: 1339726 AN: 1460126 Hom.: 617171 Cov.: 49 AF XY: 0.912 AC XY: 662541 AN XY: 726262

Gnomad4 AFR exome AF: 0.789

Gnomad4 AMR exome AF: 0.959

Gnomad4 ASJ exome AF: 0.963

Gnomad4 EAS exome AF: 0.892

Gnomad4 SAS exome AF: 0.726

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.934

Gnomad4 OTH exome AF: 0.907

GnomAD4 genome AF: 0.887 AC: 134931 AN: 152200 Hom.: 60256 Cov.: 33 AF XY: 0.883 AC XY: 65718 AN XY: 74400

Gnomad4 AFR AF: 0.792

Gnomad4 AMR AF: 0.936

Gnomad4 ASJ AF: 0.965

Gnomad4 EAS AF: 0.844

Gnomad4 SAS AF: 0.707

Gnomad4 FIN AF: 0.937

Gnomad4 NFE AF: 0.935

Gnomad4 OTH AF: 0.903

Alfa AF: 0.918 Hom.: 13222

Bravo AF: 0.889

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.24
BranchPoint Hunter		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1688030; hg19: chr19-35556744; COSMIC: COSV52884352;