rs17802279

chr15-64816305-A-Cchr15-64816305-A-Gchr15-64816305-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001286496.2(PIF1):c.1919T>G(p.Ile640Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/19 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I640N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• 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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050758272).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIF1	NM_001286496.2	c.1919T>G	p.Ile640Ser	missense_variant	13/13	ENST00000559239.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIF1	ENST00000559239.2	c.1919T>G	p.Ile640Ser	missense_variant	13/13	1	NM_001286496.2	P1
PIF1	ENST00000268043.8	c.1919T>G	p.Ile640Ser	missense_variant	13/13	1		P1
PIF1	ENST00000333425.10	c.1866+269T>G		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 59

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.97
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.42	N
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.052
Sift	Benign	0.056	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;B
Vest4		0.12
MutPred		0.18		Gain of phosphorylation at I640 (P = 0.0098);Gain of phosphorylation at I640 (P = 0.0098);
MVP		0.22
MPC		0.10
ClinPred		0.066	T
GERP RS		3.3
Varity_R		0.045

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

LitVar

Other links and lift over

dbSNP: rs17802279; hg19: chr15-65108504;