Genetic Variant PIF1:p.Arg571Leu (chr15-64816728-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001286496.2(PIF1):c.1712G>T(p.Arg571Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,456,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R571H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

PIF1
NM_001286496.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

Variant links:

Genes affected

PIF1 (HGNC:26220): (PIF1 5'-to-3' DNA helicase) This gene encodes a DNA-dependent adenosine triphosphate (ATP)-metabolizing enzyme that functions as a 5' to 3' DNA helicase. The encoded protein can resolve G-quadruplex structures and RNA-DNA hybrids at the ends of chromosomes. It also prevents telomere elongation by inhibiting the actions of telomerase. Alternative splicing and the use of alternative start codons results in multiple isoforms that are differentially localized to either the mitochondria or the nucleus. [provided by RefSeq, Nov 2013]

PIF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286496.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIF1	NM_001286496.2	MANE Select	c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	NP_001273425.1	Q9H611-1
PIF1	NM_001286497.2		c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	NP_001273426.1	Q9H611-3
PIF1	NM_025049.4		c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	NP_079325.2	Q9H611-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIF1	ENST00000559239.2	TSL:1 MANE Select	c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	ENSP00000452792.1	Q9H611-1
PIF1	ENST00000333425.10	TSL:1	c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	ENSP00000328174.6	Q9H611-3
PIF1	ENST00000268043.8	TSL:1	c.1712G>T	p.Arg571Leu	missense	Exon 12 of 13	ENSP00000268043.4	Q9H611-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

244026

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1456884

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33188

American (AMR)

AF:

0.00

AC:

AN:

43086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

85884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1110350

Other (OTH)

AF:

0.00

AC:

AN:

60166

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.053

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.46

MutationAssessor

Uncertain

2.3

PhyloP100

7.9

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.93

MutPred

0.58

Loss of sheet (P = 0.0228)

MVP

0.73

MPC

0.46

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.89

gMVP

0.69

Mutation Taster

=25/75

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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