19-35065396-A-G

Variant names:

• chr19-35065396-A-G
• rs2305746
• NM_001384133.1:c.907+51A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001384133.1(HPN):​c.907+51A>G 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 1,575,434 control chromosomes in the GnomAD database, including 662,527 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.

• Frequency:
  • Genomes: 𝑓 0.89 (60208 hom., cov: 30)
  • Exomes 𝑓: 0.92 (602319 hom.)
• Consequence: HPN NM_001384133.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.479
• Publications: 10 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: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	NM_001384133.1	MANE Select	c.907+51A>G		intron	N/A	NP_001371062.1
	HPN	NM_001375441.3		c.907+51A>G		intron	N/A	NP_001362370.1
	HPN	NM_002151.5		c.907+51A>G		intron	N/A	NP_002142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	ENST00000672452.2	MANE Select	c.907+51A>G		intron	N/A	ENSP00000500664.1
	HPN	ENST00000262626.6	TSL:1	c.907+51A>G		intron	N/A	ENSP00000262626.2
	HPN	ENST00000392226.5	TSL:1	c.907+51A>G		intron	N/A	ENSP00000376060.1

Frequencies

GnomAD3 genomes AF: 0.887 AC: 134728 AN: 151940 Hom.: 60177 Cov.: 30

Gnomad AFR AF: 0.792

Gnomad AMI AF: 0.978

Gnomad AMR AF: 0.937

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: 0.907

GnomAD2 exomes AF: 0.900 AC: 217053 AN: 241284 AF XY: 0.893

Gnomad AFR exome AF: 0.795

Gnomad AMR exome AF: 0.961

Gnomad ASJ exome AF: 0.964

Gnomad EAS exome AF: 0.850

Gnomad FIN exome AF: 0.934

Gnomad NFE exome AF: 0.938

Gnomad OTH exome AF: 0.923

GnomAD4 exome AF: 0.918 AC: 1306716 AN: 1423376 Hom.: 602319 Cov.: 23 AF XY: 0.913 AC XY: 646597 AN XY: 708372

African (AFR) AF: 0.787 AC: 25651 AN: 32580

American (AMR) AF: 0.959 AC: 42044 AN: 43826

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 24250 AN: 25170

East Asian (EAS) AF: 0.892 AC: 35127 AN: 39388

South Asian (SAS) AF: 0.727 AC: 60959 AN: 83814

European-Finnish (FIN) AF: 0.933 AC: 49456 AN: 53004

Middle Eastern (MID) AF: 0.909 AC: 5151 AN: 5666

European-Non Finnish (NFE) AF: 0.935 AC: 1010618 AN: 1081030

Other (OTH) AF: 0.908 AC: 53460 AN: 58898

GnomAD4 genome AF: 0.887 AC: 134808 AN: 152058 Hom.: 60208 Cov.: 30 AF XY: 0.883 AC XY: 65667 AN XY: 74352

African (AFR) AF: 0.792 AC: 32772 AN: 41404

American (AMR) AF: 0.937 AC: 14328 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.965 AC: 3346 AN: 3468

East Asian (EAS) AF: 0.844 AC: 4349 AN: 5154

South Asian (SAS) AF: 0.706 AC: 3404 AN: 4822

European-Finnish (FIN) AF: 0.937 AC: 9947 AN: 10612

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

European-Non Finnish (NFE) AF: 0.935 AC: 63584 AN: 67986

Other (OTH) AF: 0.905 AC: 1912 AN: 2112

Alfa AF: 0.925 Hom.: 87171

Bravo AF: 0.889

Asia WGS AF: 0.759 AC: 2641 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.7
DANN	Benign	0.55
PhyloP100		-0.48
Mutation Taster		=100/0	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: rs2305746; hg19: chr19-35556300; COSMIC: COSV52884346;