3-122540480-C-A

Variant names:

• chr3-122540480-C-A
• rs751697051
• NM_001146105.2:c.1757G>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.1757G>T​(p.Arg586Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R586H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: PARP9 NM_001146105.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.398
• Publications: 1 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=0.05785379).

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.1757G>T	p.Arg586Leu	missense	Exon 8 of 11	NP_001139577.1	Q8IXQ6-2
	PARP9	NM_001146102.2		c.1862G>T	p.Arg621Leu	missense	Exon 8 of 11	NP_001139574.1	Q8IXQ6-1
	PARP9	NM_001387871.1		c.1862G>T	p.Arg621Leu	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.1757G>T	p.Arg586Leu	missense	Exon 8 of 11	ENSP00000507390.1	Q8IXQ6-2
	PARP9	ENST00000360356.6	TSL:1	c.1862G>T	p.Arg621Leu	missense	Exon 8 of 11	ENSP00000353512.2	Q8IXQ6-1
	PARP9	ENST00000477522.6	TSL:1	c.1757G>T	p.Arg586Leu	missense	Exon 8 of 11	ENSP00000419506.1	Q8IXQ6-2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000483 AC: 2 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	2.2
DANN	Benign	0.60
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.40
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.015
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.021	B
Vest4		0.15
MutPred		0.50		Gain of sheet (P = 0.0221)
MVP		0.15
MPC		0.18
ClinPred		0.053	T
GERP RS		1.3
Varity_R		0.039
gMVP		0.26
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs751697051; hg19: chr3-122259327;