1-226392320-G-T

Variant names:

• chr1-226392320-G-T
• rs1805405
• NM_001618.4:c.287-6C>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_001618.4(PARP1):​c.287-6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.182 in 1,600,632 control chromosomes in the GnomAD database, including 28,852 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.23 (4632 hom., cov: 32)
  • Exomes 𝑓: 0.18 (24220 hom.)
• Consequence: PARP1 NM_001618.4 splice_region, intron
• Scores: Splicing: ADA: 0.03039
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.95
• Publications: 20 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-226392320-G-T is Benign according to our data. Variant chr1-226392320-G-T is described in ClinVar as Benign. ClinVar VariationId is 3059377.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 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.287-6C>A		splice_region intron	N/A	NP_001609.2	P09874

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARP1	ENST00000366794.10	TSL:1 MANE Select	c.287-6C>A		splice_region intron	N/A	ENSP00000355759.5	P09874
	PARP1	ENST00000922077.1		c.281-6C>A		splice_region intron	N/A	ENSP00000592136.1
	PARP1	ENST00000922078.1		c.287-6C>A		splice_region intron	N/A	ENSP00000592137.1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34213 AN: 151900 Hom.: 4629 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.189 AC: 47634 AN: 251420 AF XY: 0.188

Gnomad AFR exome AF: 0.383

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.337

Gnomad FIN exome AF: 0.172

Gnomad NFE exome AF: 0.168

Gnomad OTH exome AF: 0.171

GnomAD4 exome AF: 0.177 AC: 256605 AN: 1448614 Hom.: 24220 Cov.: 29 AF XY: 0.177 AC XY: 127649 AN XY: 721564

African (AFR) AF: 0.379 AC: 12604 AN: 33262

American (AMR) AF: 0.128 AC: 5731 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3762 AN: 26052

East Asian (EAS) AF: 0.328 AC: 12988 AN: 39632

South Asian (SAS) AF: 0.184 AC: 15820 AN: 85982

European-Finnish (FIN) AF: 0.169 AC: 8993 AN: 53354

Middle Eastern (MID) AF: 0.173 AC: 935 AN: 5412

European-Non Finnish (NFE) AF: 0.168 AC: 184515 AN: 1100298

Other (OTH) AF: 0.188 AC: 11257 AN: 59922

GnomAD4 genome AF: 0.225 AC: 34238 AN: 152018 Hom.: 4632 Cov.: 32 AF XY: 0.224 AC XY: 16620 AN XY: 74322

African (AFR) AF: 0.365 AC: 15124 AN: 41442

American (AMR) AF: 0.142 AC: 2174 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 480 AN: 3472

East Asian (EAS) AF: 0.338 AC: 1743 AN: 5152

South Asian (SAS) AF: 0.179 AC: 866 AN: 4826

European-Finnish (FIN) AF: 0.166 AC: 1753 AN: 10570

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.169 AC: 11491 AN: 67964

Other (OTH) AF: 0.200 AC: 423 AN: 2112

Alfa AF: 0.189 Hom.: 2403

Bravo AF: 0.233

Asia WGS AF: 0.246 AC: 859 AN: 3478

EpiCase AF: 0.167

EpiControl AF: 0.166

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PARP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	8.8
DANN	Benign	0.74
PhyloP100		1.9
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.030
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.060		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: rs1805405; hg19: chr1-226580021; COSMIC: COSV64688107; COSMIC: COSV64688107;