Variant 19-35049326-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001384133.1(HPN):c.53T>C(p.Val18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HPN
NM_001384133.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.13

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15401188).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPN	NM_001384133.1 linkuse as main transcript	c.53T>C	p.Val18Ala	missense_variant	3/13	ENST00000672452.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPN	ENST00000672452.2 linkuse as main transcript	c.53T>C	p.Val18Ala	missense_variant	3/13		NM_001384133.1	P1
HPN-AS1	ENST00000653822.1 linkuse as main transcript	n.307-3402A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441122

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The c.53T>C (p.V18A) alteration is located in exon 3 (coding exon 2) of the HPN gene. This alteration results from a T to C substitution at nucleotide position 53, causing the valine (V) at amino acid position 18 to be replaced by an alanine (A). 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

0.074

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.28

T;T;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.57

.;T;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.40

MutationAssessor

Benign

0.90

L;L;.

MutationTaster

Benign

0.57

D;D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.76

N;N;.

REVEL

Benign

0.20

Sift

Benign

0.14

T;T;.

Sift4G

Uncertain

0.058

T;T;D

Polyphen

0.26

B;B;.

Vest4

0.42

MutPred

0.26

Gain of glycosylation at P16 (P = 0.062);Gain of glycosylation at P16 (P = 0.062);Gain of glycosylation at P16 (P = 0.062);

MVP

0.55

MPC

0.73

ClinPred

0.23

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.040

gMVP

0.47

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

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over