NM_001146105.2:c.1745G>C

Variant names:

• chr3-122540492-C-G
• rs559272508
• NM_001146105.2:c.1745G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001146105.2(PARP9):​c.1745G>C​(p.Arg582Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R582L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PARP9 NM_001146105.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.20
• Publications: 0 publications found

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]

LOC105374071 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07914838).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001146105.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP9	NM_001146105.2	MANE Select	c.1745G>C	p.Arg582Pro	missense	Exon 8 of 11	NP_001139577.1	Q8IXQ6-2
	PARP9	NM_001146102.2		c.1850G>C	p.Arg617Pro	missense	Exon 8 of 11	NP_001139574.1	Q8IXQ6-1
	PARP9	NM_001387871.1		c.1850G>C	p.Arg617Pro	missense	Exon 8 of 11	NP_001374800.1	Q8IXQ6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP9	ENST00000682323.1	MANE Select	c.1745G>C	p.Arg582Pro	missense	Exon 8 of 11	ENSP00000507390.1	Q8IXQ6-2
	PARP9	ENST00000360356.6	TSL:1	c.1850G>C	p.Arg617Pro	missense	Exon 8 of 11	ENSP00000353512.2	Q8IXQ6-1
	PARP9	ENST00000477522.6	TSL:1	c.1745G>C	p.Arg582Pro	missense	Exon 8 of 11	ENSP00000419506.1	Q8IXQ6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461224 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726838

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5608

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111628

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.14
DANN	Benign	0.80
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L
PhyloP100		-2.2
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.076
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.53	P
Vest4		0.25
MutPred		0.48		Loss of MoRF binding (P = 0.0028)
MVP		0.12
MPC		0.28
ClinPred		0.20	T
GERP RS		-8.3
Varity_R		0.16
gMVP		0.56
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs559272508; hg19: chr3-122259339;