5-50759718-A-G

Position:

• chr5-50759718-A-G

Variant summary

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

The NM_024615.4(PARP8):​c.260A>G​(p.His87Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: PARP8 NM_024615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.64

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.260A>G	p.His87Arg	missense_variant	4/26	ENST00000281631.10	NP_078891.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP8	ENST00000281631.10	c.260A>G	p.His87Arg	missense_variant	4/26	1	NM_024615.4	ENSP00000281631.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000113

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

Apr 24, 2024

The c.260A>G (p.H87R) alteration is located in exon 5 (coding exon 4) of the PARP8 gene. This alteration results from a A to G substitution at nucleotide position 260, causing the histidine (H) at amino acid position 87 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	0.16
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.054	T;T;.;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.56	D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.34	N;N;N;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.2	N;N;N;D;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0090	D;D;D;T;D
Sift4G	Benign	0.063	T;T;T;D;T
Polyphen		0.93	P;P;D;.;.
Vest4		0.63
MutPred		0.40		Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);Loss of sheet (P = 0.0054);.;
MVP		0.59
MPC		0.25
ClinPred		0.92	D
GERP RS		5.3
Varity_R		0.28
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs1164330623; hg19: chr5-50055552;