1-226385663-A-G

Variant names:

• chr1-226385663-A-G
• rs1805414
• NM_001618.4:c.852T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001618.4(PARP1):​c.852T>C​(p.Ala284Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,612,866 control chromosomes in the GnomAD database, including 115,585 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (14757 hom., cov: 33)
  • Exomes 𝑓: 0.36 (100828 hom.)
• Consequence: PARP1 NM_001618.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 46 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

ENSG00000295046 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.786 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	NM_001618.4	MANE Select	c.852T>C	p.Ala284Ala	synonymous	Exon 7 of 23	NP_001609.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	ENST00000366794.10	TSL:1 MANE Select	c.852T>C	p.Ala284Ala	synonymous	Exon 7 of 23	ENSP00000355759.5
	PARP1	ENST00000922077.1		c.846T>C	p.Ala282Ala	synonymous	Exon 7 of 23	ENSP00000592136.1
	PARP1	ENST00000922078.1		c.846T>C	p.Ala282Ala	synonymous	Exon 7 of 23	ENSP00000592137.1

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64471 AN: 151942 Hom.: 14726 Cov.: 33

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.320

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.396

GnomAD2 exomes AF: 0.426 AC: 107127 AN: 251338 AF XY: 0.413

Gnomad AFR exome AF: 0.553

Gnomad AMR exome AF: 0.554

Gnomad ASJ exome AF: 0.334

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.376

GnomAD4 exome AF: 0.358 AC: 523678 AN: 1460806 Hom.: 100828 Cov.: 38 AF XY: 0.357 AC XY: 259707 AN XY: 726764

African (AFR) AF: 0.559 AC: 18681 AN: 33438

American (AMR) AF: 0.538 AC: 24050 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.330 AC: 8616 AN: 26132

East Asian (EAS) AF: 0.793 AC: 31494 AN: 39700

South Asian (SAS) AF: 0.369 AC: 31836 AN: 86248

European-Finnish (FIN) AF: 0.403 AC: 21539 AN: 53406

Middle Eastern (MID) AF: 0.334 AC: 1925 AN: 5766

European-Non Finnish (NFE) AF: 0.327 AC: 362770 AN: 1111042

Other (OTH) AF: 0.377 AC: 22767 AN: 60356

GnomAD4 genome AF: 0.425 AC: 64564 AN: 152060 Hom.: 14757 Cov.: 33 AF XY: 0.429 AC XY: 31862 AN XY: 74320

African (AFR) AF: 0.543 AC: 22530 AN: 41482

American (AMR) AF: 0.458 AC: 7002 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1139 AN: 3470

East Asian (EAS) AF: 0.807 AC: 4167 AN: 5166

South Asian (SAS) AF: 0.380 AC: 1828 AN: 4812

European-Finnish (FIN) AF: 0.401 AC: 4236 AN: 10560

Middle Eastern (MID) AF: 0.313 AC: 92 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22540 AN: 67984

Other (OTH) AF: 0.396 AC: 835 AN: 2110

Alfa AF: 0.363 Hom.: 6979

Bravo AF: 0.439

Asia WGS AF: 0.546 AC: 1900 AN: 3478

EpiCase AF: 0.320

EpiControl AF: 0.326

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.037
DANN	Benign	0.39
PhyloP100		-2.6
Mutation Taster		=99/1	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: rs1805414; hg19: chr1-226573364; COSMIC: COSV64689261; COSMIC: COSV64689261;