Genetic Variant PARP4:p.Ala1469Gly (chr13-24434735-G-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006437.4(PARP4):c.4406C>G(p.Ala1469Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,613,896 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0056 ( 39 hom. )

Consequence

PARP4
NM_006437.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.82

Variant links:

Genes affected

PARP4 (HGNC:271): (poly(ADP-ribose) polymerase family member 4) This gene encodes poly(ADP-ribosyl)transferase-like 1 protein, which is capable of catalyzing a poly(ADP-ribosyl)ation reaction. This protein has a catalytic domain which is homologous to that of poly (ADP-ribosyl) transferase, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of poly (ADP-ribosyl) transferase. Since this protein is not capable of binding DNA directly, its transferase activity may be activated by other factors such as protein-protein interaction mediated by the extensive carboxyl terminus. [provided by RefSeq, Jul 2008]

PARP4 links:

TPTE2P6 (HGNC:42644): (TPTE2 pseudogene 6)

TPTE2P6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070907474).

BP6

Variant 13-24434735-G-C is Benign according to our data. Variant chr13-24434735-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2643685.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP4	NM_006437.4 link	c.4406C>G	p.Ala1469Gly	missense_variant	Exon 31 of 34	ENST00000381989.4	NP_006428.2	Q9UKK3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PARP4	ENST00000381989.4 link	c.4406C>G	p.Ala1469Gly	missense_variant	Exon 31 of 34	1	NM_006437.4	ENSP00000371419.3		Q9UKK3
TPTE2P6	ENST00000445572.5 link	n.233+25431G>C		intron_variant	Intron 3 of 9	6

Frequencies

GnomAD3 genomes

AF:

0.00352

AC:

535

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00559

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00315

AC:

787

AN:

249842

Hom.:

AF XY:

0.00311

AC XY:

421

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.00102

Gnomad AMR exome

AF:

0.00290

Gnomad ASJ exome

AF:

0.000498

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00245

Gnomad NFE exome

AF:

0.00524

Gnomad OTH exome

AF:

0.00313

GnomAD4 exome

AF:

0.00560

AC:

8191

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

3961

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.000650

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00271

Gnomad4 NFE exome

AF:

0.00684

Gnomad4 OTH exome

AF:

0.00404

GnomAD4 genome

AF:

0.00351

AC:

535

AN:

152286

Hom.:

Cov.:

AF XY:

0.00321

AC XY:

239

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00559

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00348

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00306

AC:

372

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00562

EpiControl

AF:

0.00611

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PARP4: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.76

DANN

Benign

0.70

DEOGEN2

Benign

0.043

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.52

M_CAP

Benign

0.00052

MetaRNN

Benign

0.0071

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.55

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.010

REVEL

Benign

0.014

Sift

Benign

0.38

Sift4G

Benign

0.41

Polyphen

0.0

Vest4

0.11

MVP

0.31

MPC

0.13

ClinPred

0.0028

GERP RS

-5.6

Varity_R

0.016

gMVP

0.10

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

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