chr19-35065253-A-G

Variant summary

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

The NM_001384133.1(HPN):ā€‹c.815A>Gā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000027 ( 0 hom. )

Consequence

HPN
NM_001384133.1 missense

Scores

1
11
7

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-AS1 (HGNC:47041): (HPN antisense RNA 1)

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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
HPNNM_001384133.1 linkuse as main transcriptc.815A>G p.Tyr272Cys missense_variant 10/13 ENST00000672452.2
HPN-AS1NR_024562.1 linkuse as main transcriptn.405-5475T>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HPNENST00000672452.2 linkuse as main transcriptc.815A>G p.Tyr272Cys missense_variant 10/13 NM_001384133.1 P1
HPN-AS1ENST00000653822.1 linkuse as main transcriptn.213-12134T>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1459436
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
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.:
32

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 submitterclinical testingAmbry GeneticsAug 26, 2022The 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
D
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
D;D;.
Eigen
Uncertain
0.33
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.82
.;T;T
M_CAP
Uncertain
0.14
D
MetaRNN
Benign
0.38
T;T;T
MetaSVM
Uncertain
0.41
D
MutationAssessor
Benign
1.6
L;L;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.70
T
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
D
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.

Other links and lift over

hg19: chr19-35556157; API