19-35060635-G-C

Variant names:

• chr19-35060635-G-C
• rs2064519712
• NM_001384133.1:c.629G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001384133.1(HPN):​c.629G>C​(p.Arg210Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R210Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPN NM_001384133.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

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.629G>C	p.Arg210Pro	missense	Exon 9 of 13	NP_001371062.1	P05981
	HPN	NM_001375441.3		c.629G>C	p.Arg210Pro	missense	Exon 9 of 13	NP_001362370.1	A0A140VJK9
	HPN	NM_002151.5		c.629G>C	p.Arg210Pro	missense	Exon 10 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.629G>C	p.Arg210Pro	missense	Exon 9 of 13	ENSP00000500664.1	P05981
	HPN	ENST00000262626.6	TSL:1	c.629G>C	p.Arg210Pro	missense	Exon 9 of 13	ENSP00000262626.2	P05981
	HPN	ENST00000392226.5	TSL:1	c.629G>C	p.Arg210Pro	missense	Exon 10 of 14	ENSP00000376060.1	P05981

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.87	L
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.66
Sift	Benign	0.19	T
Sift4G	Benign	0.30	T
Polyphen		1.0	D
Vest4		0.67
MutPred		0.49		Loss of MoRF binding (P = 6e-04)
MVP		0.85
MPC		1.2
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.84
gMVP		0.94
Mutation Taster		=46/54	disease causing

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: rs2064519712; hg19: chr19-35551539;