Genetic Variant NM_006437.4:c.5065C>T (chr13-24421229-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006437.4(PARP4):c.5065C>T(p.Arg1689Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000442 in 1,381,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PARP4
NM_006437.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.26

Publications

0 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006437.4. 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
	PARP4	NM_006437.4	MANE Select	c.5065C>T	p.Arg1689Trp	missense	Exon 34 of 34	NP_006428.2	Q9UKK3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PARP4	ENST00000381989.4	TSL:1 MANE Select	c.5065C>T	p.Arg1689Trp	missense	Exon 34 of 34	ENSP00000371419.3	Q9UKK3
PARP4	ENST00000908086.1		c.5065C>T	p.Arg1689Trp	missense	Exon 35 of 35	ENSP00000578145.1
PARP4	ENST00000934618.1		c.5065C>T	p.Arg1689Trp	missense	Exon 35 of 35	ENSP00000604677.1

Frequencies

GnomAD3 genomes

AF:

0.0000469

AC:

AN:

149158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000744

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000593

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000628

AC:

AN:

79610

AF XY:

0.0000762

show subpopulations

Gnomad AFR exome

AF:

0.000162

Gnomad AMR exome

AF:

0.000166

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000662

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1232292

Hom.:

Cov.:

AF XY:

0.0000364

AC XY:

AN XY:

604622

show subpopulations

African (AFR)

AF:

0.0000369

AC:

AN:

27100

American (AMR)

AF:

0.0000818

AC:

AN:

24464

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19456

East Asian (EAS)

AF:

0.0000287

AC:

AN:

34794

South Asian (SAS)

AF:

0.0000320

AC:

AN:

62424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45718

Middle Eastern (MID)

AF:

0.000285

AC:

AN:

3506

European-Non Finnish (NFE)

AF:

0.0000457

AC:

AN:

963262

Other (OTH)

AF:

0.0000582

AC:

AN:

51568

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000469

AC:

AN:

149158

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

72558

show subpopulations

African (AFR)

AF:

0.0000744

AC:

AN:

40314

American (AMR)

AF:

0.00

AC:

AN:

14880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3442

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.00

AC:

AN:

4578

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000593

AC:

AN:

67474

Other (OTH)

AF:

0.00

AC:

AN:

2008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000976

Hom.:

ExAC

AF:

0.0000665

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.82

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.72

MutationAssessor

Uncertain

2.5

PhyloP100

2.3

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.6

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.62

MVP

0.94

MPC

0.57

ClinPred

0.88

GERP RS

3.2

Varity_R

0.34

gMVP

0.70

Mutation Taster

=79/21

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over