rs1136410

Positions:

• chr1-226367601-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000366794.10(PARP1):​c.2285T>C​(p.Val762Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,852 control chromosomes in the GnomAD database, including 27,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (2595 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24640 hom.)
• Consequence: PARP1 ENST00000366794.10 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.94

Genes affected

PARP1 (HGNC:270): (poly(ADP-ribose) polymerase 1) This gene encodes a chromatin-associated enzyme, poly(ADP-ribosyl)transferase, which modifies various nuclear proteins by poly(ADP-ribosyl)ation. The modification is dependent on DNA and is involved in the regulation of various important cellular processes such as differentiation, proliferation, and tumor transformation and also in the regulation of the molecular events involved in the recovery of cell from DNA damage. In addition, this enzyme may be the site of mutation in Fanconi anemia, and may participate in the pathophysiology of type I diabetes. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029218793).
• BP6: Variant 1-226367601-A-G is Benign according to our data. Variant chr1-226367601-A-G is described in ClinVar as [Benign]. Clinvar id is 1261945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.414 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PARP1	NM_001618.4	c.2285T>C	p.Val762Ala	missense_variant	17/23	ENST00000366794.10	NP_001609.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PARP1	ENST00000366794.10	c.2285T>C	p.Val762Ala	missense_variant	17/23	1	NM_001618.4	ENSP00000355759	P1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23915 AN: 152050 Hom.: 2589 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.302

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.429

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.234

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.164

GnomAD3 exomes AF: 0.213 AC: 53567 AN: 251412 Hom.: 7750 AF XY: 0.200 AC XY: 27205 AN XY: 135878

Gnomad AFR exome AF: 0.0487

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.160

Gnomad EAS exome AF: 0.448

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.234

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.169 AC: 247339 AN: 1461684 Hom.: 24640 Cov.: 33 AF XY: 0.167 AC XY: 121143 AN XY: 727168

Gnomad4 AFR exome AF: 0.0486

Gnomad4 AMR exome AF: 0.402

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.420

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.169

GnomAD4 genome AF: 0.157 AC: 23938 AN: 152168 Hom.: 2595 Cov.: 32 AF XY: 0.163 AC XY: 12120 AN XY: 74384

Gnomad4 AFR AF: 0.0539

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.158

Gnomad4 EAS AF: 0.429

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.234

Gnomad4 NFE AF: 0.159

Gnomad4 OTH AF: 0.166

Alfa AF: 0.165 Hom.: 6011

Bravo AF: 0.162

TwinsUK AF: 0.147 AC: 544

ALSPAC AF: 0.159 AC: 612

ESP6500AA AF: 0.0529 AC: 233

ESP6500EA AF: 0.159 AC: 1371

ExAC AF: 0.202 AC: 24493

Asia WGS AF: 0.229 AC: 798 AN: 3478

EpiCase AF: 0.149

EpiControl AF: 0.155

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2019	This variant is associated with the following publications: (PMID: 24392019, 29484706, 23633189, 15342424, 23040216, 24853559, 24489833, 22624032, 23608917, 23073772, 18716896, 23910651, 19484672, 18054108, 21037106, 20196871, 17214964) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	5.5e-11	P
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.18
Sift	Benign	0.18	T
Sift4G	Benign	0.51	T
Polyphen		0.73	P
Vest4		0.31
MPC		0.84
ClinPred		0.055	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.58
gMVP		0.50

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: rs1136410; hg19: chr1-226555302; COSMIC: COSV64689246; COSMIC: COSV64689246;