NM_001286496.2:c.1844G>A

Variant names:

• chr15-64816596-C-T
• rs78139154
• NM_001286496.2:c.1844G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001286496.2(PIF1):​c.1844G>A​(p.Arg615Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,678 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (63 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (78 hom.)
• Consequence: PIF1 NM_001286496.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.194
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023785532).
• BP6: Variant 15-64816596-C-T is Benign according to our data. Variant chr15-64816596-C-T is described in ClinVar as Benign. ClinVar VariationId is 787119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0508 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.1844G>A	p.Arg615Gln	missense	Exon 12 of 13	NP_001273425.1	Q9H611-1
	PIF1	NM_001286497.2		c.1844G>A	p.Arg615Gln	missense	Exon 12 of 13	NP_001273426.1	Q9H611-3
	PIF1	NM_025049.4		c.1844G>A	p.Arg615Gln	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.1844G>A	p.Arg615Gln	missense	Exon 12 of 13	ENSP00000452792.1	Q9H611-1
	PIF1	ENST00000333425.10	TSL:1	c.1844G>A	p.Arg615Gln	missense	Exon 12 of 13	ENSP00000328174.6	Q9H611-3
	PIF1	ENST00000268043.8	TSL:1	c.1844G>A	p.Arg615Gln	missense	Exon 12 of 13	ENSP00000268043.4	Q9H611-1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2249 AN: 152214 Hom.: 62 Cov.: 33

Gnomad AFR AF: 0.0525

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00375 AC: 938 AN: 249846 AF XY: 0.00280

Gnomad AFR exome AF: 0.0532

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00156 AC: 2283 AN: 1461346 Hom.: 78 Cov.: 32 AF XY: 0.00135 AC XY: 982 AN XY: 727030

African (AFR) AF: 0.0576 AC: 1926 AN: 33438

American (AMR) AF: 0.00211 AC: 94 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5760

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111874

Other (OTH) AF: 0.00287 AC: 173 AN: 60370

GnomAD4 genome AF: 0.0148 AC: 2259 AN: 152332 Hom.: 63 Cov.: 33 AF XY: 0.0142 AC XY: 1059 AN XY: 74492

African (AFR) AF: 0.0526 AC: 2186 AN: 41566

American (AMR) AF: 0.00327 AC: 50 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68028

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00576 Hom.: 27

Bravo AF: 0.0163

ESP6500AA AF: 0.0486 AC: 214

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00467 AC: 567

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.7
DANN	Benign	0.97
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.19
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.099
Sift	Benign	0.10	T
Sift4G	Benign	0.088	T
Polyphen		0.051	B
Vest4		0.20
MVP		0.26
MPC		0.081
ClinPred		0.023	T
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.26
Mutation Taster		=96/4	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: rs78139154; hg19: chr15-65108795; COSMIC: COSV51424997; COSMIC: COSV51424997;