13-24435303-C-G

Position:

• chr13-24435303-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006437.4(PARP4):​c.3838G>C​(p.Gly1280Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,611,868 control chromosomes in the GnomAD database, including 110,993 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.40 (12242 hom., cov: 32)
  • Exomes 𝑓: 0.37 (98751 hom.)
• Consequence: PARP4 NM_006437.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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]

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

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.3983588E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP4	NM_006437.4	c.3838G>C	p.Gly1280Arg	missense_variant	31/34	ENST00000381989.4	NP_006428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP4	ENST00000381989.4	c.3838G>C	p.Gly1280Arg	missense_variant	31/34	1	NM_006437.4	ENSP00000371419	P1
TPTE2P6	ENST00000445572.5	n.233+25999C>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60302 AN: 151964 Hom.: 12216 Cov.: 32

Gnomad AFR AF: 0.462

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.379

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.366 AC: 92026 AN: 251192 Hom.: 17166 AF XY: 0.363 AC XY: 49227 AN XY: 135764

Gnomad AFR exome AF: 0.463

Gnomad AMR exome AF: 0.316

Gnomad ASJ exome AF: 0.372

Gnomad EAS exome AF: 0.353

Gnomad SAS exome AF: 0.304

Gnomad FIN exome AF: 0.423

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.366 AC: 534560 AN: 1459786 Hom.: 98751 Cov.: 37 AF XY: 0.364 AC XY: 264338 AN XY: 726252

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.324

Gnomad4 ASJ exome AF: 0.368

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.366

GnomAD4 genome AF: 0.397 AC: 60378 AN: 152082 Hom.: 12242 Cov.: 32 AF XY: 0.395 AC XY: 29400 AN XY: 74356

Gnomad4 AFR AF: 0.462

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.379

Gnomad4 EAS AF: 0.356

Gnomad4 SAS AF: 0.298

Gnomad4 FIN AF: 0.433

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.396

Alfa AF: 0.336 Hom.: 2671

Bravo AF: 0.391

TwinsUK AF: 0.372 AC: 1379

ALSPAC AF: 0.358 AC: 1379

ESP6500AA AF: 0.471 AC: 2076

ESP6500EA AF: 0.373 AC: 3204

ExAC AF: 0.369 AC: 44760

Asia WGS AF: 0.382 AC: 1327 AN: 3478

EpiCase AF: 0.372

EpiControl AF: 0.369

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.22
DANN	Benign	0.53
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.00034	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.0070
Sift	Benign	0.42	T
Sift4G	Benign	0.072	T
Polyphen		0.21	B
Vest4		0.044
MPC		0.15
ClinPred		0.0012	T
GERP RS		-1.3
Varity_R		0.025
gMVP		0.18

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

Other links and lift over

dbSNP: rs13428; hg19: chr13-25009441; COSMIC: COSV67960420;