rs1021627126

Variant names:

• chr19-35049323-A-G
• rs1021627126
• NM_001384133.1:c.50A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001384133.1(HPN):​c.50A>G​(p.Lys17Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,439,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K17N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HPN NM_001384133.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.110164285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384133.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	NM_001384133.1	MANE Select	c.50A>G	p.Lys17Arg	missense	Exon 3 of 13	NP_001371062.1	P05981
	HPN	NM_001375441.3		c.50A>G	p.Lys17Arg	missense	Exon 3 of 13	NP_001362370.1	A0A140VJK9
	HPN	NM_002151.5		c.50A>G	p.Lys17Arg	missense	Exon 4 of 14	NP_002142.1	P05981

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HPN	ENST00000672452.2	MANE Select	c.50A>G	p.Lys17Arg	missense	Exon 3 of 13	ENSP00000500664.1	P05981
	HPN	ENST00000262626.6	TSL:1	c.50A>G	p.Lys17Arg	missense	Exon 3 of 13	ENSP00000262626.2	P05981
	HPN	ENST00000392226.5	TSL:1	c.50A>G	p.Lys17Arg	missense	Exon 4 of 14	ENSP00000376060.1	P05981

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235588 AF XY: 0.00000790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000938

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000347 AC: 5 AN: 1439528 Hom.: 0 Cov.: 32 AF XY: 0.00000421 AC XY: 3 AN XY: 713312

African (AFR) AF: 0.00 AC: 0 AN: 33168

American (AMR) AF: 0.00 AC: 0 AN: 43276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24588

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.00 AC: 0 AN: 82986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000364 AC: 4 AN: 1099106

Other (OTH) AF: 0.0000168 AC: 1 AN: 59412

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.16
Sift	Benign	0.56	T
Sift4G	Benign	0.74	T
Polyphen		0.0	B
Vest4		0.36
MutPred		0.24		Loss of ubiquitination at K17 (P = 0.0381)
MVP		0.66
MPC		0.49
ClinPred		0.050	T
GERP RS		2.7
Varity_R		0.027
gMVP		0.40
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1021627126; hg19: chr19-35540227;