Genetic Variant PROK1:p.Arg48Trp (chr1-110454030-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032414.3(PROK1):c.142C>T(p.Arg48Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00347 in 1,614,090 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.017 ( 70 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 60 hom. )

Consequence

PROK1
NM_032414.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.501

Publications

6 publications found

Variant links:

Genes affected

PROK1 (HGNC:18454): (prokineticin 1) The protein encoded by this gene induces proliferation, migration, and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. It has little or no effect on a variety of other endothelial and non-endothelial cell types. Its expression is restricted to the steroidogenic glands (ovary, testis, adrenal, and placenta), is induced by hypoxia, and often complementary to the expression of vascular endothelial growth factor (VEGF), suggesting that these molecules function in a coordinated manner. [provided by RefSeq, Sep 2011]

PROK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0060395002).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0573 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK1	NM_032414.3 link	c.142C>T	p.Arg48Trp	missense_variant	Exon 2 of 3	ENST00000271331.4	NP_115790.1	P58294A0A024R0B1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK1	ENST00000271331.4 link	c.142C>T	p.Arg48Trp	missense_variant	Exon 2 of 3	1	NM_032414.3	ENSP00000271331.3		P58294

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2657

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0593

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00863

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00520

AC:

1305

AN:

251170

AF XY:

0.00388

show subpopulations

Gnomad AFR exome

AF:

0.0643

Gnomad AMR exome

AF:

0.00489

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00202

AC:

2947

AN:

1461774

Hom.:

Cov.:

AF XY:

0.00181

AC XY:

1316

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0594

AC:

1988

AN:

33478

American (AMR)

AF:

0.00519

AC:

232

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000332

AC:

369

AN:

1112002

Other (OTH)

AF:

0.00500

AC:

302

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

158

315

473

630

788

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0175

AC:

2660

AN:

152316

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1221

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.0592

AC:

2462

AN:

41572

American (AMR)

AF:

0.00856

AC:

131

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

67998

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

129

257

386

514

643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00392

Hom.:

Bravo

AF:

0.0206

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0635

AC:

280

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00616

AC:

748

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000771

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0060

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.2

PhyloP100

0.50

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.59

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.66

MVP

0.97

MPC

0.39

ClinPred

0.047

GERP RS

3.3

Varity_R

0.54

gMVP

0.82

Mutation Taster

=39/61

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over