15-64816305-A-T

Position:

• chr15-64816305-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/19 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.39 (12279 hom., cov: 31)
  • Exomes 𝑓: 0.43 (139304 hom.)
• Consequence: PIF1 NM_001286496.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.544

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
PIF1	NM_001286496.2	c.1919T>A	p.Ile640Asn	missense_variant	13/13	ENST00000559239.2	NP_001273425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIF1	ENST00000559239.2	c.1919T>A	p.Ile640Asn	missense_variant	13/13	1	NM_001286496.2	ENSP00000452792.1
PIF1	ENST00000268043.8	c.1919T>A	p.Ile640Asn	missense_variant	13/13	1		ENSP00000268043.4
PIF1	ENST00000333425.10	c.1866+269T>A		intron_variant		1		ENSP00000328174.6

Frequencies

GnomAD3 genomes AF: 0.388 AC: 58851 AN: 151740 Hom.: 12260 Cov.: 31

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

GnomAD3 exomes AF: 0.374 AC: 93896 AN: 251076 Hom.: 19727 AF XY: 0.381 AC XY: 51683 AN XY: 135700

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 SAS exome AF: 0.292

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.: 59 AF XY: 0.425 AC XY: 308719 AN XY: 727098

Gnomad4 AFR exome AF: 0.281

Gnomad4 AMR exome AF: 0.234

Gnomad4 ASJ exome AF: 0.466

Gnomad4 EAS exome AF: 0.0849

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.509

Gnomad4 NFE exome AF: 0.459

Gnomad4 OTH exome AF: 0.411

GnomAD4 genome AF: 0.388 AC: 58902 AN: 151858 Hom.: 12279 Cov.: 31 AF XY: 0.389 AC XY: 28871 AN XY: 74220

Gnomad4 AFR AF: 0.289

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.459

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.533

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.393

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	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.24
DEOGEN2	Benign	0.021	T;T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.26	.;T
MetaRNN	Benign	0.00055	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N;N
PrimateAI	Uncertain	0.48	T
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	T
GERP RS		3.3
Varity_R		0.069

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

LitVar

Other links and lift over

dbSNP: rs17802279; hg19: chr15-65108504; COSMIC: COSV51421804; COSMIC: COSV51421804;