Genetic Variant NM_001286496.2:c.1919T>A (chr15-64816305-A-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001286496.2(PIF1):c.1919T>A(p.Ile640Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,613,446 control chromosomes in the GnomAD database, including 151,583 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. I640V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.39 ( 12279 hom., cov: 31)

Exomes 𝑓: 0.43 ( 139304 hom. )

Consequence

PIF1
NM_001286496.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.544

Publications

29 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=5.540252E-4).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIF1	NM_001286496.2 link	c.1919T>A	p.Ile640Asn	missense_variant	Exon 13 of 13	ENST00000559239.2	NP_001273425.1	Q9H611-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PIF1	ENST00000559239.2 link	c.1919T>A	p.Ile640Asn	missense_variant	Exon 13 of 13	1	NM_001286496.2	ENSP00000452792.1	Q9H611-1
PIF1	ENST00000268043.8 link	c.1919T>A	p.Ile640Asn	missense_variant	Exon 13 of 13	1		ENSP00000268043.4	Q9H611-1
PIF1	ENST00000333425.10 link	c.1866+269T>A		intron_variant	Intron 12 of 12	1		ENSP00000328174.6	Q9H611-3

Frequencies

GnomAD3 genomes

AF:

0.388

AC:

58851

AN:

151740

Hom.:

12260

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.543

Gnomad AMR

AF:

0.338

Gnomad ASJ

AF:

0.459

Gnomad EAS

AF:

0.116

Gnomad SAS

AF:

0.269

Gnomad FIN

AF:

0.533

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.460

Gnomad OTH

AF:

0.399

GnomAD2 exomes

AF:

0.374

AC:

93896

AN:

251076

AF XY:

0.381

show subpopulations

Gnomad AFR exome

AF:

0.290

Gnomad AMR exome

AF:

0.221

Gnomad ASJ exome

AF:

0.469

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.511

Gnomad NFE exome

AF:

0.460

Gnomad OTH exome

AF:

0.413

GnomAD4 exome

AF:

0.427

AC:

624813

AN:

1461588

Hom.:

139304

Cov.:

AF XY:

0.425

AC XY:

308719

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.281

AC:

9408

AN:

33478

American (AMR)

AF:

0.234

AC:

10482

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.466

AC:

12185

AN:

26132

East Asian (EAS)

AF:

0.0849

AC:

3371

AN:

39700

South Asian (SAS)

AF:

0.292

AC:

25153

AN:

86232

European-Finnish (FIN)

AF:

0.509

AC:

27145

AN:

53304

Middle Eastern (MID)

AF:

0.384

AC:

2201

AN:

5730

European-Non Finnish (NFE)

AF:

0.459

AC:

510066

AN:

1111908

Other (OTH)

AF:

0.411

AC:

24802

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

20896

41792

62687

83583

104479

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14900

29800

44700

59600

74500

<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

AF:

0.388

AC:

58902

AN:

151858

Hom.:

12279

Cov.:

AF XY:

0.389

AC XY:

28871

AN XY:

74220

show subpopulations

African (AFR)

AF:

0.289

AC:

11956

AN:

41414

American (AMR)

AF:

0.337

AC:

5148

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.459

AC:

1592

AN:

3468

East Asian (EAS)

AF:

0.116

AC:

596

AN:

5158

South Asian (SAS)

AF:

0.271

AC:

1306

AN:

4812

European-Finnish (FIN)

AF:

0.533

AC:

5621

AN:

10554

Middle Eastern (MID)

AF:

0.395

AC:

116

AN:

294

European-Non Finnish (NFE)

AF:

0.460

AC:

31241

AN:

67876

Other (OTH)

AF:

0.393

AC:

831

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1784

3568

5352

7136

8920

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

560

1120

1680

2240

2800

<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:

0.437

Hom.:

10003

Bravo

AF:

0.370

TwinsUK

AF:

0.467

AC:

1731

ALSPAC

AF:

0.461

AC:

1777

ESP6500AA

AF:

0.308

AC:

1355

ESP6500EA

AF:

0.463

AC:

3983

ExAC

AF:

0.377

AC:

45718

Asia WGS

AF:

0.208

AC:

728

AN:

3478

EpiCase

AF:

0.465

EpiControl

AF:

0.459

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.041

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.021

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.26

.;T

MetaRNN

Benign

0.00055

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.1

N;N

PhyloP100

0.54

PrimateAI

Uncertain

0.48

PROVEAN

Benign

1.4

N;N

REVEL

Benign

0.061

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.053

MPC

0.13

ClinPred

0.0018

GERP RS

3.3

Varity_R

0.069

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over