NM_001146105.2:c.1745G>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001146105.2(PARP9):​c.1745G>T​(p.Arg582Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PARP9 NM_001146105.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039834768).

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>T	p.Arg582Leu	missense	Exon 8 of 11	NP_001139577.1	Q8IXQ6-2
	PARP9	NM_001146102.2		c.1850G>T	p.Arg617Leu	missense	Exon 8 of 11	NP_001139574.1	Q8IXQ6-1
	PARP9	NM_001387871.1		c.1850G>T	p.Arg617Leu	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>T	p.Arg582Leu	missense	Exon 8 of 11	ENSP00000507390.1	Q8IXQ6-2
	PARP9	ENST00000360356.6	TSL:1	c.1850G>T	p.Arg617Leu	missense	Exon 8 of 11	ENSP00000353512.2	Q8IXQ6-1
	PARP9	ENST00000477522.6	TSL:1	c.1745G>T	p.Arg582Leu	missense	Exon 8 of 11	ENSP00000419506.1	Q8IXQ6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0070
DANN	Benign	0.77
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0016	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.40	N
PhyloP100		-2.2
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.025
Sift	Benign	0.22	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.095
MutPred		0.41		Loss of loop (P = 0.0084)
MVP		0.088
MPC		0.18
ClinPred		0.081	T
GERP RS		-8.3
Varity_R		0.028
gMVP		0.23
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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;