19-35060635-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPN NM_001384133.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPN	NM_001384133.1	c.629G>C	p.Arg210Pro	missense_variant	Exon 9 of 13	ENST00000672452.2	NP_001371062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HPN	ENST00000672452.2	c.629G>C	p.Arg210Pro	missense_variant	Exon 9 of 13		NM_001384133.1	ENSP00000500664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	.;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.87	L;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Pathogenic	0.66
Sift	Benign	0.19	T;T;.
Sift4G	Benign	0.30	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.67
MutPred		0.49		Loss of MoRF binding (P = 6e-04);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2064519712; hg19: chr19-35551539;