10-49819357-G-T

Position:

• chr10-49819357-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003631.5(PARG):​c.2914C>A​(p.Gln972Lys) 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. 12/15 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: PARG NM_003631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054727674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARG	NM_003631.5	c.2914C>A	p.Gln972Lys	missense_variant	18/18	ENST00000616448.2	NP_003622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARG	ENST00000616448.2	c.2914C>A	p.Gln972Lys	missense_variant	18/18	1	NM_003631.5	ENSP00000484285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Mar 29, 2023

The c.2914C>A (p.Q972K) alteration is located in exon (coding exon ) of the PARG gene. This alteration results from a C to A substitution at nucleotide position 2914, causing the glutamine (Q) at amino acid position 972 to be replaced by a lysine (K). 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	0.060
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.067	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	.;T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.32	T
REVEL	Benign	0.032
Sift4G	Benign	0.43	T;T
Polyphen		0.0	B;B
Vest4		0.035
MutPred		0.20		Gain of ubiquitination at Q972 (P = 0.0037);Gain of ubiquitination at Q972 (P = 0.0037);
MVP		0.32
ClinPred		0.18	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.048
gMVP		0.38

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: rs1843951239; hg19: chr10-51027403;