1-151017828-A-G

Position:

chr1-151017828-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_021222.3(PRUNE1):c.56A>G(p.His19Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,597,306 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

PRUNE1
NM_021222.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.74

Variant links:

Genes affected

PRUNE1 (HGNC:13420): (prune exopolyphosphatase 1) This gene encodes a member of the DHH protein superfamily of phosphoesterases. This protein has been found to function as both a nucleotide phosphodiesterase and an exopolyphosphatase. This protein is believed to stimulate cancer progression and metastases through the induction of cell motility. A pseuodgene has been identified on chromosome 13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

PRUNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.097776264).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000539 (82/152092) while in subpopulation NFE AF= 0.00107 (73/67998). AF 95% confidence interval is 0.000876. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRUNE1	NM_021222.3 linkuse as main transcript	c.56A>G	p.His19Arg	missense_variant	2/8	ENST00000271620.8	NP_067045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRUNE1	ENST00000271620.8 linkuse as main transcript	c.56A>G	p.His19Arg	missense_variant	2/8	1	NM_021222.3	ENSP00000271620	P1	Q86TP1-1

Frequencies

GnomAD3 genomes

AF:

0.000540

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000946

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000565

AC:

142

AN:

251344

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00119

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00101

AC:

1456

AN:

1445214

Hom.:

Cov.:

AF XY:

0.000956

AC XY:

688

AN XY:

719884

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0000768

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000244

Gnomad4 NFE exome

AF:

0.00128

Gnomad4 OTH exome

AF:

0.000569

GnomAD4 genome

AF:

0.000539

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000946

Gnomad4 NFE

AF:

0.00107

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000978

Hom.:

Bravo

AF:

0.000499

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000436

AC:

EpiCase

AF:

0.000982

EpiControl

AF:

0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 30, 2022	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 19 of the PRUNE1 protein (p.His19Arg). This variant is present in population databases (rs138499343, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PRUNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1029812). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 28, 2023	BS1 -

Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 11, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.76

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.8

.;D

REVEL

Benign

0.28

Sift

Benign

0.19

.;T

Sift4G

Benign

0.11

.;T

Polyphen

1.0

.;D

Vest4

0.84

MVP

0.49

MPC

0.79

ClinPred

0.31

GERP RS

3.6

Varity_R

0.45

gMVP

0.65

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

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