Variant chr10-49857437-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003631.5(PARG):c.2222G>A(p.Arg741His) variant causes a missense change. The variant allele was found at a frequency of 0.0000391 in 1,612,530 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 25)

Exomes 𝑓: 0.000039 ( 1 hom. )

Consequence

PARG
NM_003631.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.85

Variant links:

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 links:

PARG (HGNC:):

PARG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARG	NM_003631.5 linkuse as main transcript	c.2222G>A	p.Arg741His	missense_variant	13/18	ENST00000616448.2	NP_003622.2	Q86W56-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARG	ENST00000616448.2 linkuse as main transcript	c.2222G>A	p.Arg741His	missense_variant	13/18	1	NM_003631.5	ENSP00000484285.1		Q86W56-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000167

AC:

AN:

240160

Hom.:

AF XY:

0.0000231

AC XY:

AN XY:

129810

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:

0.00

Gnomad FIN exome

AF:

0.0000475

Gnomad NFE exome

AF:

0.0000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1460438

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726436

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:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.0000302

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 submitter

clinical testing

Ambry Genetics

Sep 20, 2023

The c.2222G>A (p.R741H) alteration is located in exon 13 (coding exon 13) of the PARG gene. This alteration results from a G to A substitution at nucleotide position 2222, causing the arginine (R) at amino acid position 741 to be replaced by a histidine (H). 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

Benign

0.26

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

D;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

.;T

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

-0.00090

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Pathogenic

0.82

REVEL

Pathogenic

0.74

Sift4G

Uncertain

0.0070

D;D

Polyphen

1.0

D;D

Vest4

0.69

MutPred

0.74

Loss of methylation at R741 (P = 0.0539);Loss of methylation at R741 (P = 0.0539);

MVP

0.37

ClinPred

0.97

GERP RS

4.4

Varity_R

0.31

gMVP

0.56

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over