rs149970077

Variant names:

• chr19-35049296-G-A
• rs149970077
• NM_001384133.1:c.23G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001384133.1(HPN):​c.23G>A​(p.Arg8Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000404 in 1,550,780 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: HPN NM_001384133.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.206
• Publications: 3 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061219335).
• BP6: Variant 19-35049296-G-A is Benign according to our data. Variant chr19-35049296-G-A is described in ClinVar as Benign. ClinVar VariationId is 716476.Status of the report is criteria_provided_single_submitter, 1 stars.

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.23G>A	p.Arg8Gln	missense	Exon 3 of 13	NP_001371062.1	P05981
	HPN	NM_001375441.3		c.23G>A	p.Arg8Gln	missense	Exon 3 of 13	NP_001362370.1	A0A140VJK9
	HPN	NM_002151.5		c.23G>A	p.Arg8Gln	missense	Exon 4 of 14	NP_002142.1	P05981

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	ENST00000672452.2	MANE Select	c.23G>A	p.Arg8Gln	missense	Exon 3 of 13	ENSP00000500664.1	P05981
	HPN	ENST00000262626.6	TSL:1	c.23G>A	p.Arg8Gln	missense	Exon 3 of 13	ENSP00000262626.2	P05981
	HPN	ENST00000392226.5	TSL:1	c.23G>A	p.Arg8Gln	missense	Exon 4 of 14	ENSP00000376060.1	P05981

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152234 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000665 AC: 139 AN: 208876 AF XY: 0.000504

Gnomad AFR exome AF: 0.00818

Gnomad AMR exome AF: 0.000138

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000559

Gnomad NFE exome AF: 0.0000519

Gnomad OTH exome AF: 0.000202

GnomAD4 exome AF: 0.000246 AC: 344 AN: 1398428 Hom.: 1 Cov.: 32 AF XY: 0.000217 AC XY: 149 AN XY: 687604

African (AFR) AF: 0.00806 AC: 259 AN: 32150

American (AMR) AF: 0.000283 AC: 11 AN: 38870

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22240

East Asian (EAS) AF: 0.00 AC: 0 AN: 38740

South Asian (SAS) AF: 0.00 AC: 0 AN: 76452

European-Finnish (FIN) AF: 0.0000404 AC: 2 AN: 49556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5440

European-Non Finnish (NFE) AF: 0.0000529 AC: 57 AN: 1077356

Other (OTH) AF: 0.000260 AC: 15 AN: 57624

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152352 Hom.: 1 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74508

African (AFR) AF: 0.00642 AC: 267 AN: 41594

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000574 Hom.: 1

Bravo AF: 0.00219

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000677 AC: 82

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.26	N
PhyloP100		-0.21
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.23
Sift	Benign	0.058	T
Sift4G	Benign	0.13	T
Polyphen		0.0010	B
Vest4		0.38
MVP		0.67
MPC		0.69
ClinPred		0.019	T
GERP RS		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.048
gMVP		0.22
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149970077; hg19: chr19-35540200; COSMIC: COSV52883303; COSMIC: COSV52883303;