10-49842045-G-A

Position:

• chr10-49842045-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003631.5(PARG):​c.2446C>T​(p.Arg816Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PARG NM_003631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.37

Genes affected

PARG (HGNC:8605): (poly(ADP-ribose) glycohydrolase) Poly(ADP-ribose) glycohydrolase (PARG) is the major enzyme responsible for the catabolism of poly(ADP-ribose), a reversible covalent-modifier of chromosomal proteins. The protein is found in many tissues and may be subject to proteolysis generating smaller, active products. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

PARG (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARG	NM_003631.5	c.2446C>T	p.Arg816Trp	missense_variant	15/18	ENST00000616448.2	NP_003622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARG	ENST00000616448.2	c.2446C>T	p.Arg816Trp	missense_variant	15/18	1	NM_003631.5	ENSP00000484285.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396172 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 688748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 21, 2023

The c.2446C>T (p.R816W) alteration is located in exon (coding exon ) of the PARG gene. This alteration results from a C to T substitution at nucleotide position 2446, causing the arginine (R) at amino acid position 816 to be replaced by a tryptophan (W). 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	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	.;D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.4	M;M
PrimateAI	Uncertain	0.56	T
REVEL	Uncertain	0.56
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.85
MutPred		0.90		Loss of disorder (P = 0.0429);Loss of disorder (P = 0.0429);
MVP		0.50
ClinPred		0.93	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.95

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

Other links and lift over

dbSNP: rs1554832457; hg19: chr10-51050091;