Genetic Variant PARP4:p.Ser1685Phe (chr13-24421240-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006437.4(PARP4):c.5054C>T(p.Ser1685Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000401 in 1,346,192 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000038 ( 1 hom. )

Consequence

PARP4
NM_006437.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.97

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PARP4	NM_006437.4 link	c.5054C>T	p.Ser1685Phe	missense_variant	Exon 34 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.5054C>T	p.Ser1685Phe	missense_variant	Exon 34 of 34	1	NM_006437.4	ENSP00000371419.3		Q9UKK3
TPTE2P6	ENST00000445572.5 link	n.233+11936G>A		intron_variant	Intron 3 of 9	6

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

149220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000674

Gnomad ASJ

AF:

0.000579

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000445

Gnomad OTH

AF:

0.000996

GnomAD3 exomes

AF:

0.0000257

AC:

AN:

77742

Hom.:

AF XY:

0.0000260

AC XY:

AN XY:

38526

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000890

GnomAD4 exome

AF:

0.0000384

AC:

AN:

1196972

Hom.:

Cov.:

AF XY:

0.0000459

AC XY:

AN XY:

587768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000427

Gnomad4 ASJ exome

AF:

0.000211

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000326

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000398

GnomAD4 genome

AF:

0.0000536

AC:

AN:

149220

Hom.:

Cov.:

AF XY:

0.0000551

AC XY:

AN XY:

72596

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000674

Gnomad4 ASJ

AF:

0.000579

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000445

Gnomad4 OTH

AF:

0.000996

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PARP4: PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.79

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.51

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.4

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.9

REVEL

Uncertain

0.58

Sift

Uncertain

0.011

Sift4G

Uncertain

0.043

Polyphen

1.0

Vest4

0.47

MVP

0.92

MPC

0.58

ClinPred

0.94

GERP RS

3.2

Varity_R

0.14

gMVP

0.44

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

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