chr19-35059974-C-T

Variant names:

• chr19-35059974-C-T
• rs45512696
• NM_001384133.1:c.391C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001384133.1(HPN):​c.391C>T​(p.Leu131Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,563,892 control chromosomes in the GnomAD database, including 18,793 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 0.10 (1166 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17627 hom.)
• Consequence: HPN NM_001384133.1 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 13 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP7: Synonymous conserved (PhyloP=-0.086 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 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.391C>T	p.Leu131Leu	synonymous	Exon 6 of 13	NP_001371062.1
	HPN	NM_001375441.3		c.391C>T	p.Leu131Leu	synonymous	Exon 6 of 13	NP_001362370.1
	HPN	NM_002151.5		c.391C>T	p.Leu131Leu	synonymous	Exon 7 of 14	NP_002142.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	ENST00000672452.2	MANE Select	c.391C>T	p.Leu131Leu	synonymous	Exon 6 of 13	ENSP00000500664.1
	HPN	ENST00000262626.6	TSL:1	c.391C>T	p.Leu131Leu	synonymous	Exon 6 of 13	ENSP00000262626.2
	HPN	ENST00000392226.5	TSL:1	c.391C>T	p.Leu131Leu	synonymous	Exon 7 of 14	ENSP00000376060.1

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15901 AN: 152132 Hom.: 1166 Cov.: 33

Gnomad AFR AF: 0.0284

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.0909

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.0875

GnomAD2 exomes AF: 0.114 AC: 23969 AN: 209436 AF XY: 0.119

Gnomad AFR exome AF: 0.0267

Gnomad AMR exome AF: 0.0635

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.00981

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.152 AC: 214799 AN: 1411642 Hom.: 17627 Cov.: 34 AF XY: 0.151 AC XY: 104940 AN XY: 695912

African (AFR) AF: 0.0252 AC: 816 AN: 32318

American (AMR) AF: 0.0648 AC: 2589 AN: 39952

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2417 AN: 22552

East Asian (EAS) AF: 0.0196 AC: 770 AN: 39252

South Asian (SAS) AF: 0.101 AC: 7838 AN: 77286

European-Finnish (FIN) AF: 0.156 AC: 7960 AN: 51102

Middle Eastern (MID) AF: 0.0715 AC: 394 AN: 5514

European-Non Finnish (NFE) AF: 0.170 AC: 184092 AN: 1085570

Other (OTH) AF: 0.136 AC: 7923 AN: 58096

GnomAD4 genome AF: 0.104 AC: 15899 AN: 152250 Hom.: 1166 Cov.: 33 AF XY: 0.103 AC XY: 7664 AN XY: 74446

African (AFR) AF: 0.0283 AC: 1178 AN: 41562

American (AMR) AF: 0.0776 AC: 1187 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 357 AN: 3470

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5178

South Asian (SAS) AF: 0.0914 AC: 441 AN: 4826

European-Finnish (FIN) AF: 0.162 AC: 1718 AN: 10618

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10635 AN: 67972

Other (OTH) AF: 0.0870 AC: 184 AN: 2114

Alfa AF: 0.126 Hom.: 1100

Bravo AF: 0.0960

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.86
PhyloP100		-0.086
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs45512696; hg19: chr19-35550878; COSMIC: COSV52882676; COSMIC: COSV52882676;