Genetic Variant PARP1:p.Phe638Leu (chr1-226377135-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001618.4(PARP1):c.1914C>A(p.Phe638Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,186 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F638F) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

PARP1
NM_001618.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.29

Publications

4 publications found

Variant links:

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

PARP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.1914C>A	p.Phe638Leu	missense	Exon 13 of 23	NP_001609.2	P09874

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PARP1	ENST00000366794.10	TSL:1 MANE Select	c.1914C>A	p.Phe638Leu	missense	Exon 13 of 23	ENSP00000355759.5	P09874
PARP1	ENST00000922077.1		c.1908C>A	p.Phe636Leu	missense	Exon 13 of 23	ENSP00000592136.1
PARP1	ENST00000922078.1		c.1908C>A	p.Phe636Leu	missense	Exon 13 of 23	ENSP00000592137.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.0000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

Eigen

Benign

-0.074

Eigen_PC

Benign

0.078

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.74

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

PhyloP100

5.3

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.27

Sift

Uncertain

0.013

Sift4G

Benign

0.49

Polyphen

0.038

Vest4

0.90

MutPred

0.59

Gain of catalytic residue at F638 (P = 0.0147)

MVP

0.63

MPC

0.28

ClinPred

0.95

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.81

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over