15-64816623-C-G

Variant names:

• chr15-64816623-C-G
• rs773939962
• NM_001286496.2:c.1817G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001286496.2(PIF1):​c.1817G>C​(p.Arg606Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 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. R606H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PIF1 NM_001286496.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	NP_001273425.1	Q9H611-1
	PIF1	NM_001286497.2		c.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	NP_001273426.1	Q9H611-3
	PIF1	NM_025049.4		c.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	NP_079325.2	Q9H611-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIF1	ENST00000559239.2	TSL:1 MANE Select	c.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	ENSP00000452792.1	Q9H611-1
	PIF1	ENST00000333425.10	TSL:1	c.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	ENSP00000328174.6	Q9H611-3
	PIF1	ENST00000268043.8	TSL:1	c.1817G>C	p.Arg606Pro	missense	Exon 12 of 13	ENSP00000268043.4	Q9H611-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.5
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.26	T
Sift4G	Benign	0.26	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.49		Loss of MoRF binding (P = 0.0068)
MVP		0.57
MPC		0.44
ClinPred		0.84	D
GERP RS		4.0
Varity_R		0.89
gMVP		0.69

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: rs773939962; hg19: chr15-65108822;