5-50795257-T-C

Position:

• chr5-50795257-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024615.4(PARP8):​c.1268T>C​(p.Leu423Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PARP8 NM_024615.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.57

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP8	NM_024615.4	c.1268T>C	p.Leu423Pro	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.1268T>C	p.Leu423Pro	missense_variant	12/26	1	NM_024615.4	ENSP00000281631.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Feb 17, 2024

The c.1268T>C (p.L423P) alteration is located in exon 13 (coding exon 12) of the PARP8 gene. This alteration results from a T to C substitution at nucleotide position 1268, causing the leucine (L) at amino acid position 423 to be replaced by a proline (P). 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	0.42
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.051	T;T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Pathogenic	0.76	D;D;D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.4	L;.;L;L;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.57	N;N;N;N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Benign	0.19	T;D;T;T;T
Polyphen		1.0	D;.;D;D;.
Vest4		0.96
MutPred		0.22		Loss of stability (P = 0.0025);.;Loss of stability (P = 0.0025);Loss of stability (P = 0.0025);.;
MVP		0.68
MPC		0.94
ClinPred		0.93	D
GERP RS		5.3
Varity_R		0.40
gMVP		0.75

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: chr5-50091091;