1-226363128-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001618.4(PARP1):c.2819A>G(p.Lys940Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,613,868 control chromosomes in the GnomAD database, including 432 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 0.0051 (27 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (405 hom.)
• Consequence: PARP1 NM_001618.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.99

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030174851).
• BP6: Variant 1-226363128-T-C is Benign according to our data. Variant chr1-226363128-T-C is described in ClinVar as [Benign]. Clinvar id is 3041509.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0771 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PARP1	NM_001618.4	c.2819A>G	p.Lys940Arg	missense_variant	21/23	ENST00000366794.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PARP1	ENST00000366794.10	c.2819A>G	p.Lys940Arg	missense_variant	21/23	1	NM_001618.4	P1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152190 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.00227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.0378

Gnomad SAS AF: 0.0840

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.0124 AC: 3116 AN: 251478 Hom.: 126 AF XY: 0.0158 AC XY: 2154 AN XY: 135908

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00923

Gnomad EAS exome AF: 0.0285

Gnomad SAS exome AF: 0.0771

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000457

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.00663 AC: 9690 AN: 1461560 Hom.: 405 Cov.: 30 AF XY: 0.00870 AC XY: 6325 AN XY: 727114

Gnomad4 AFR exome AF: 0.00290

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00861

Gnomad4 EAS exome AF: 0.0453

Gnomad4 SAS exome AF: 0.0760

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.00833

GnomAD4 genome AF: 0.00508 AC: 773 AN: 152308 Hom.: 27 Cov.: 32 AF XY: 0.00666 AC XY: 496 AN XY: 74476

Gnomad4 AFR AF: 0.00226

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.0381

Gnomad4 SAS AF: 0.0839

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000367

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00160 Hom.: 1

Bravo AF: 0.00311

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.0135 AC: 1634

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

PARP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.013	D
Polyphen		0.88	P
Vest4		0.18
MPC		0.22
ClinPred		0.028	T
GERP RS		5.8
Varity_R		0.86
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3219145; hg19: chr1-226550829;