1-226390398-T-C

Variant names:

• chr1-226390398-T-C
• rs1805403
• NM_001618.4:c.617+12A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001618.4(PARP1):​c.617+12A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.79 in 1,611,530 control chromosomes in the GnomAD database, including 506,133 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 0.83 (53472 hom., cov: 31)
  • Exomes 𝑓: 0.79 (452661 hom.)
• Consequence: PARP1 NM_001618.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -5.75
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.931 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.617+12A>G		intron	N/A	NP_001609.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	ENST00000366794.10	TSL:1 MANE Select	c.617+12A>G		intron	N/A	ENSP00000355759.5
	PARP1	ENST00000922077.1		c.611+12A>G		intron	N/A	ENSP00000592136.1
	PARP1	ENST00000922078.1		c.611+12A>G		intron	N/A	ENSP00000592137.1

Frequencies

GnomAD3 genomes AF: 0.834 AC: 126790 AN: 152022 Hom.: 53408 Cov.: 31

Gnomad AFR AF: 0.938

Gnomad AMI AF: 0.796

Gnomad AMR AF: 0.823

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.940

Gnomad SAS AF: 0.753

Gnomad FIN AF: 0.878

Gnomad MID AF: 0.737

Gnomad NFE AF: 0.773

Gnomad OTH AF: 0.804

GnomAD2 exomes AF: 0.810 AC: 203319 AN: 251036 AF XY: 0.800

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.870

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.939

Gnomad FIN exome AF: 0.880

Gnomad NFE exome AF: 0.768

Gnomad OTH exome AF: 0.775

GnomAD4 exome AF: 0.786 AC: 1146982 AN: 1459390 Hom.: 452661 Cov.: 39 AF XY: 0.783 AC XY: 568479 AN XY: 726040

African (AFR) AF: 0.945 AC: 31568 AN: 33422

American (AMR) AF: 0.861 AC: 38508 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 18517 AN: 26124

East Asian (EAS) AF: 0.934 AC: 37059 AN: 39694

South Asian (SAS) AF: 0.742 AC: 63917 AN: 86170

European-Finnish (FIN) AF: 0.873 AC: 46580 AN: 53386

Middle Eastern (MID) AF: 0.691 AC: 3279 AN: 4746

European-Non Finnish (NFE) AF: 0.774 AC: 860291 AN: 1110898

Other (OTH) AF: 0.785 AC: 47263 AN: 60232

GnomAD4 genome AF: 0.834 AC: 126914 AN: 152140 Hom.: 53472 Cov.: 31 AF XY: 0.839 AC XY: 62416 AN XY: 74390

African (AFR) AF: 0.938 AC: 38967 AN: 41524

American (AMR) AF: 0.823 AC: 12555 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2439 AN: 3472

East Asian (EAS) AF: 0.940 AC: 4856 AN: 5166

South Asian (SAS) AF: 0.753 AC: 3637 AN: 4828

European-Finnish (FIN) AF: 0.878 AC: 9303 AN: 10594

Middle Eastern (MID) AF: 0.738 AC: 217 AN: 294

European-Non Finnish (NFE) AF: 0.773 AC: 52516 AN: 67978

Other (OTH) AF: 0.806 AC: 1700 AN: 2110

Alfa AF: 0.787 Hom.: 8714

Bravo AF: 0.835

Asia WGS AF: 0.856 AC: 2977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.028
DANN	Benign	0.33
PhyloP100		-5.7
Mutation Taster		=100/0	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: rs1805403; hg19: chr1-226578099;