Genetic Variant PARP4:p.Ala1469Val (chr13-24434735-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006437.4(PARP4):c.4406C>T(p.Ala1469Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1469G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PARP4
NM_006437.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.82

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06586629).

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.4406C>T	p.Ala1469Val	missense	Exon 31 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.4406C>T	p.Ala1469Val	missense	Exon 31 of 34	ENSP00000371419.3	Q9UKK3
PARP4	ENST00000908086.1		c.4406C>T	p.Ala1469Val	missense	Exon 32 of 35	ENSP00000578145.1
PARP4	ENST00000934618.1		c.4406C>T	p.Ala1469Val	missense	Exon 32 of 35	ENSP00000604677.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111920

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.12

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.019

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0022

LIST_S2

Benign

0.53

M_CAP

Benign

0.00047

MetaRNN

Benign

0.066

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

-1.8

PrimateAI

Benign

0.24

PROVEAN

Benign

0.050

REVEL

Benign

0.017

Sift

Benign

0.37

Sift4G

Benign

0.55

Polyphen

0.0040

Vest4

0.027

MutPred

0.26

Gain of catalytic residue at Q1465 (P = 0.0028)

MVP

0.31

MPC

0.11

ClinPred

0.049

GERP RS

-5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

0.95

Varity_R

0.015

gMVP

0.089

Mutation Taster

=100/0

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over