13-24434543-T-C

Position:

• chr13-24434543-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006437.4(PARP4):​c.4598A>G​(p.Gln1533Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PARP4 NM_006437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.88

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05112493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP4	NM_006437.4	c.4598A>G	p.Gln1533Arg	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.4598A>G	p.Gln1533Arg	missense_variant	31/34	1	NM_006437.4	ENSP00000371419	P1
TPTE2P6	ENST00000445572.5	n.233+25239T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.4598A>G (p.Q1533R) alteration is located in exon 31 (coding exon 30) of the PARP4 gene. This alteration results from a A to G substitution at nucleotide position 4598, causing the glutamine (Q) at amino acid position 1533 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.0010
DANN	Benign	0.20
DEOGEN2	Benign	0.023	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.00065	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.0050
Sift	Benign	0.48	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.026
MutPred		0.21		Gain of phosphorylation at S1535 (P = 0.0838);
MVP		0.20
MPC		0.12
ClinPred		0.031	T
GERP RS		-5.4
Varity_R		0.018
gMVP		0.093

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-25008681;