15-64816333-C-G

Variant names:

• chr15-64816333-C-G
• rs141363784
• NM_001286496.2:c.1891G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001286496.2(PIF1):​c.1891G>C​(p.Ala631Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,614,038 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (28 hom.)
• Consequence: PIF1 NM_001286496.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0280
• Publications: 0 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=0.0043348074).
• BP6: Variant 15-64816333-C-G is Benign according to our data. Variant chr15-64816333-C-G is described in ClinVar as Benign. ClinVar VariationId is 776913.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1525/152228) while in subpopulation AFR AF = 0.0353 (1466/41506). AF 95% confidence interval is 0.0338. There are 33 homozygotes in GnomAd4. There are 689 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 gene

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.1891G>C	p.Ala631Pro	missense	Exon 13 of 13	NP_001273425.1	Q9H611-1
	PIF1	NM_025049.4		c.1891G>C	p.Ala631Pro	missense	Exon 13 of 13	NP_079325.2	Q9H611-1
	PIF1	NM_001286499.2		c.1732G>C	p.Ala578Pro	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.1891G>C	p.Ala631Pro	missense	Exon 13 of 13	ENSP00000452792.1	Q9H611-1
	PIF1	ENST00000268043.8	TSL:1	c.1891G>C	p.Ala631Pro	missense	Exon 13 of 13	ENSP00000268043.4	Q9H611-1
	PIF1	ENST00000333425.10	TSL:1	c.1866+241G>C		intron	N/A	ENSP00000328174.6	Q9H611-3

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1523 AN: 152110 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.00267 AC: 672 AN: 251348 AF XY: 0.00190

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00107 AC: 1561 AN: 1461810 Hom.: 28 Cov.: 34 AF XY: 0.000925 AC XY: 673 AN XY: 727206

African (AFR) AF: 0.0379 AC: 1268 AN: 33478

American (AMR) AF: 0.00168 AC: 75 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1112000

Other (OTH) AF: 0.00228 AC: 138 AN: 60396

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152228 Hom.: 33 Cov.: 33 AF XY: 0.00926 AC XY: 689 AN XY: 74440

African (AFR) AF: 0.0353 AC: 1466 AN: 41506

American (AMR) AF: 0.00255 AC: 39 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68012

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.00353 Hom.: 6

Bravo AF: 0.0118

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0386 AC: 170

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00324 AC: 393

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

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	0.081
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.92
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.028
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.031
Sift	Benign	0.29	T
Sift4G	Benign	0.29	T
Polyphen		0.10	B
Vest4		0.20
MVP		0.092
MPC		0.16
ClinPred		0.00060	T
GERP RS		-0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.069
Mutation Taster		=100/0	polymorphism

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: rs141363784; hg19: chr15-65108532; COSMIC: COSV107266169; COSMIC: COSV107266169;