19-35059960-C-T

Variant names:

• chr19-35059960-C-T
• NM_001384133.1:c.377C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001384133.1(HPN):​c.377C>T​(p.Pro126Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HPN NM_001384133.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HPN	NM_001384133.1	c.377C>T	p.Pro126Leu	missense_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	c.377C>T	p.Pro126Leu	missense_variant	Exon 6 of 13		NM_001384133.1	ENSP00000500664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.377C>T (p.P126L) alteration is located in exon 6 (coding exon 5) of the HPN gene. This alteration results from a C to T substitution at nucleotide position 377, causing the proline (P) at amino acid position 126 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T
Eigen	Benign	-0.071
Eigen_PC	Benign	0.0088
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.86	.;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	M;M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.26
Sift	Benign	0.073	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.42	B;B
Vest4		0.51
MutPred		0.94		Gain of catalytic residue at P126 (P = 0.1275);Gain of catalytic residue at P126 (P = 0.1275);
MVP		0.50
MPC		0.70
ClinPred		0.91	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-35550864;