chr3-122528656-A-G

Variant summary

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

The NM_001146105.2(PARP9):ā€‹c.2168T>Cā€‹(p.Leu723Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

PARP9
NM_001146105.2 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89
Variant links:
Genes affected
PARP9 (HGNC:24118): (poly(ADP-ribose) polymerase family member 9) Enables several functions, including ADP-D-ribose binding activity; NAD+ ADP-ribosyltransferase activity; and STAT family protein binding activity. Involved in several processes, including positive regulation of nitrogen compound metabolic process; regulation of defense response; and regulation of gene expression. Located in several cellular components, including mitochondrion; nucleoplasm; and site of DNA damage. Part of protein-containing complex. Colocalizes with nucleus. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
PARP9NM_001146105.2 linkuse as main transcriptc.2168T>C p.Leu723Pro missense_variant 11/11 ENST00000682323.1 NP_001139577.1 Q8IXQ6-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PARP9ENST00000682323.1 linkuse as main transcriptc.2168T>C p.Leu723Pro missense_variant 11/11 NM_001146105.2 ENSP00000507390.1 Q8IXQ6-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251338
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 12, 2021The c.2273T>C (p.L758P) alteration is located in exon 11 (coding exon 10) of the PARP9 gene. This alteration results from a T to C substitution at nucleotide position 2273, causing the leucine (L) at amino acid position 758 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
0.37
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.040
.;T;T;.
Eigen
Benign
-0.11
Eigen_PC
Benign
-0.33
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.69
.;T;T;T
M_CAP
Benign
0.0085
T
MetaRNN
Uncertain
0.49
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.7
.;.;M;.
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.6
D;D;D;D
REVEL
Benign
0.18
Sift
Uncertain
0.011
D;D;D;D
Sift4G
Uncertain
0.040
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.60
MutPred
0.56
.;.;Loss of stability (P = 0.0154);.;
MVP
0.21
MPC
0.79
ClinPred
0.90
D
GERP RS
2.2
Varity_R
0.62
gMVP
0.78

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs762252030; hg19: chr3-122247503; API