5-50795235-A-G

Position:

• chr5-50795235-A-G

Variant summary

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

The NM_024615.4(PARP8):​c.1246A>G​(p.Arg416Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PARP8 NM_024615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.280

Genes affected

PARP8 (HGNC:26124): (poly(ADP-ribose) polymerase family member 8) Enables protein ADP-ribosylase activity. Involved in protein auto-ADP-ribosylation and protein mono-ADP-ribosylation. [provided by Alliance of Genome Resources, Apr 2022]

PARP8 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
PARP8	NM_024615.4	c.1246A>G	p.Arg416Gly	missense_variant	12/26	ENST00000281631.10	NP_078891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP8	ENST00000281631.10	c.1246A>G	p.Arg416Gly	missense_variant	12/26	1	NM_024615.4	ENSP00000281631.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 17, 2022

The c.1246A>G (p.R416G) alteration is located in exon 13 (coding exon 12) of the PARP8 gene. This alteration results from a A to G substitution at nucleotide position 1246, causing the arginine (R) at amino acid position 416 to be replaced by a glycine (G). 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	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.045	T;T;T;.;T
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.94	.;D;D;D;D
M_CAP	Benign	0.0094	T
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.2	L;.;L;L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.99	D;.;D;D;.
Vest4		0.90
MutPred		0.34		Loss of MoRF binding (P = 0.018);.;Loss of MoRF binding (P = 0.018);Loss of MoRF binding (P = 0.018);.;
MVP		0.69
MPC		0.41
ClinPred		0.92	D
GERP RS		-2.9
Varity_R		0.48
gMVP		0.65

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-50091069;