NM_001618.4:c.2285T>C

Variant names:

• chr1-226367601-A-G
• rs1136410
• NM_001618.4:c.2285T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001618.4(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2595 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24640 hom.)
• Consequence: PARP1 NM_001618.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 8.94
• Publications: 352 publications found

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]

PARP1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001618.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	NM_001618.4	MANE Select	c.2285T>C	p.Val762Ala	missense	Exon 17 of 23	NP_001609.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	ENST00000366794.10	TSL:1 MANE Select	c.2285T>C	p.Val762Ala	missense	Exon 17 of 23	ENSP00000355759.5
	PARP1	ENST00000922077.1		c.2279T>C	p.Val760Ala	missense	Exon 17 of 23	ENSP00000592136.1
	PARP1	ENST00000922078.1		c.2279T>C	p.Val760Ala	missense	Exon 17 of 23	ENSP00000592137.1

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

GnomAD2 exomes AF: 0.213 AC: 53567 AN: 251412 AF XY: 0.200

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 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

African (AFR) AF: 0.0486 AC: 1627 AN: 33480

American (AMR) AF: 0.402 AC: 17961 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 4083 AN: 26136

East Asian (EAS) AF: 0.420 AC: 16686 AN: 39692

South Asian (SAS) AF: 0.107 AC: 9196 AN: 86254

European-Finnish (FIN) AF: 0.233 AC: 12447 AN: 53360

Middle Eastern (MID) AF: 0.149 AC: 857 AN: 5768

European-Non Finnish (NFE) AF: 0.157 AC: 174261 AN: 1111880

Other (OTH) AF: 0.169 AC: 10221 AN: 60394

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

African (AFR) AF: 0.0539 AC: 2238 AN: 41546

American (AMR) AF: 0.303 AC: 4631 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 550 AN: 3472

East Asian (EAS) AF: 0.429 AC: 2213 AN: 5162

South Asian (SAS) AF: 0.112 AC: 542 AN: 4820

European-Finnish (FIN) AF: 0.234 AC: 2477 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10834 AN: 67986

Other (OTH) AF: 0.166 AC: 349 AN: 2108

Alfa AF: 0.163 Hom.: 8395

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.9
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
Mutation Taster		=66/34	polymorphism (auto)

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

Other links and lift over

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