NM_001286496.2:c.1919T>A

Variant names:

• chr15-64816305-A-T
• rs17802279
• NM_001286496.2:c.1919T>A

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.544
• Publications: 29 publications found

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

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIF1	NM_001286496.2	MANE Select	c.1919T>A	p.Ile640Asn	missense	Exon 13 of 13	NP_001273425.1	Q9H611-1
	PIF1	NM_025049.4		c.1919T>A	p.Ile640Asn	missense	Exon 13 of 13	NP_079325.2	Q9H611-1
	PIF1	NM_001286499.2		c.1760T>A	p.Ile587Asn	missense	Exon 13 of 13	NP_001273428.1	Q9H611-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIF1	ENST00000559239.2	TSL:1 MANE Select	c.1919T>A	p.Ile640Asn	missense	Exon 13 of 13	ENSP00000452792.1	Q9H611-1
	PIF1	ENST00000268043.8	TSL:1	c.1919T>A	p.Ile640Asn	missense	Exon 13 of 13	ENSP00000268043.4	Q9H611-1
	PIF1	ENST00000333425.10	TSL:1	c.1866+269T>A		intron	N/A	ENSP00000328174.6	Q9H611-3

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

GnomAD2 exomes AF: 0.374 AC: 93896 AN: 251076 AF XY: 0.381

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

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

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

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

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 v4.9

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
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
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.54
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.13
ClinPred		0.0018	T
GERP RS		3.3
Varity_R		0.069
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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