Genetic Variant HPN:p.Leu131Leu (chr19-35059974-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0860

Variant links:

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 links:

HPN-AS1 (HGNC:47041): (HPN antisense RNA 1)

HPN-AS1 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPN	NM_001384133.1 link	c.391C>T	p.Leu131Leu	synonymous_variant	Exon 6 of 13	ENST00000672452.2	NP_001371062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPN	ENST00000672452.2 link	c.391C>T	p.Leu131Leu	synonymous_variant	Exon 6 of 13		NM_001384133.1	ENSP00000500664.1		P05981

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15901

AN:

152132

Hom.:

1166

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.151

AC XY:

104940

AN XY:

695912

show subpopulations

Gnomad4 AFR exome

AF:

0.0252

AC:

816

AN:

32318

Gnomad4 AMR exome

AF:

0.0648

AC:

2589

AN:

39952

Gnomad4 ASJ exome

AF:

0.107

AC:

2417

AN:

22552

Gnomad4 EAS exome

AF:

0.0196

AC:

770

AN:

39252

Gnomad4 SAS exome

AF:

0.101

AC:

7838

AN:

77286

Gnomad4 FIN exome

AF:

0.156

AC:

7960

AN:

51102

Gnomad4 NFE exome

AF:

0.170

AC:

184092

AN:

1085570

Gnomad4 Remaining exome

AF:

0.136

AC:

7923

AN:

58096

Heterozygous variant carriers

10136

20271

30407

40542

50678

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

6588

13176

19764

26352

32940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.104

AC:

15899

AN:

152250

Hom.:

1166

Cov.:

AF XY:

0.103

AC XY:

7664

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0283

AC:

0.0283432

AN:

0.0283432

Gnomad4 AMR

AF:

0.0776

AC:

0.0775614

AN:

0.0775614

Gnomad4 ASJ

AF:

0.103

AC:

0.102882

AN:

0.102882

Gnomad4 EAS

AF:

0.0120

AC:

0.0119737

AN:

0.0119737

Gnomad4 SAS

AF:

0.0914

AC:

0.09138

AN:

0.09138

Gnomad4 FIN

AF:

0.162

AC:

0.161801

AN:

0.161801

Gnomad4 NFE

AF:

0.156

AC:

0.156461

AN:

0.156461

Gnomad4 OTH

AF:

0.0870

AC:

0.0870388

AN:

0.0870388

Heterozygous variant carriers

732

1464

2196

2928

3660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

182

364

546

728

910

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.86

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over