Variant 19-35065253-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001384133.1(HPN):c.815A>G(p.Tyr272Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

HPN
NM_001384133.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.44

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3832365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HPN	NM_001384133.1 linkuse as main transcript	c.815A>G	p.Tyr272Cys	missense_variant	10/13	ENST00000672452.2
HPN-AS1	NR_024562.1 linkuse as main transcript	n.405-5475T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HPN	ENST00000672452.2 linkuse as main transcript	c.815A>G	p.Tyr272Cys	missense_variant	10/13		NM_001384133.1	P1
HPN-AS1	ENST00000653822.1 linkuse as main transcript	n.213-12134T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459436

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726016

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

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

Aug 26, 2022

The c.815A>G (p.Y272C) alteration is located in exon 10 (coding exon 9) of the HPN gene. This alteration results from a A to G substitution at nucleotide position 815, causing the tyrosine (Y) at amino acid position 272 to be replaced by a cysteine (C). 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

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.095

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.75

D;D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.82

.;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.38

T;T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.6

L;L;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Uncertain

0.62

Sift

Benign

0.044

D;D;.

Sift4G

Benign

0.11

T;T;T

Polyphen

0.98

D;D;.

Vest4

0.47

MutPred

0.57

Loss of phosphorylation at Y272 (P = 0.0827);Loss of phosphorylation at Y272 (P = 0.0827);.;

MVP

0.64

MPC

1.1

ClinPred

0.96

GERP RS

5.4

Varity_R

0.54

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over