19-35065840-T-C

Variant names:

• chr19-35065840-T-C
• rs1688030
• NM_001384133.1:c.1051-28T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 17 publications found

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:47041): (HPN antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384133.1. 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
	HPN	NM_001384133.1	MANE Select	c.1051-28T>C		intron	N/A	NP_001371062.1	P05981
	HPN	NM_001375441.3		c.1051-28T>C		intron	N/A	NP_001362370.1	A0A140VJK9
	HPN	NM_002151.5		c.1051-28T>C		intron	N/A	NP_002142.1	P05981

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	ENST00000672452.2	MANE Select	c.1051-28T>C		intron	N/A	ENSP00000500664.1	P05981
	HPN	ENST00000262626.6	TSL:1	c.1051-28T>C		intron	N/A	ENSP00000262626.2	P05981
	HPN	ENST00000392226.5	TSL:1	c.1051-28T>C		intron	N/A	ENSP00000376060.1	P05981

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

GnomAD2 exomes AF: 0.899 AC: 224756 AN: 250030 AF XY: 0.892

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 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

African (AFR) AF: 0.789 AC: 26379 AN: 33448

American (AMR) AF: 0.959 AC: 42859 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 25146 AN: 26106

East Asian (EAS) AF: 0.892 AC: 35390 AN: 39674

South Asian (SAS) AF: 0.726 AC: 62599 AN: 86180

European-Finnish (FIN) AF: 0.933 AC: 49416 AN: 52950

Middle Eastern (MID) AF: 0.910 AC: 4861 AN: 5342

European-Non Finnish (NFE) AF: 0.934 AC: 1038401 AN: 1111446

Other (OTH) AF: 0.907 AC: 54675 AN: 60288

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

African (AFR) AF: 0.792 AC: 32885 AN: 41512

American (AMR) AF: 0.936 AC: 14332 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3348 AN: 3470

East Asian (EAS) AF: 0.844 AC: 4355 AN: 5160

South Asian (SAS) AF: 0.707 AC: 3407 AN: 4822

European-Finnish (FIN) AF: 0.937 AC: 9942 AN: 10606

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63586 AN: 68006

Other (OTH) AF: 0.903 AC: 1910 AN: 2114

Alfa AF: 0.916 Hom.: 13480

Bravo AF: 0.889

Asia WGS AF: 0.758 AC: 2637 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	10
DANN	Benign	0.24
PhyloP100		0.060
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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