chr15-64816333-C-G

Position:

• chr15-64816333-C-G

Variant summary

Our verdict is Benign. Variant got -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. 15/19 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

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 Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 33 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIF1	NM_001286496.2	c.1891G>C	p.Ala631Pro	missense_variant	13/13	ENST00000559239.2	NP_001273425.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIF1	ENST00000559239.2	c.1891G>C	p.Ala631Pro	missense_variant	13/13	1	NM_001286496.2	ENSP00000452792.1
PIF1	ENST00000268043.8	c.1891G>C	p.Ala631Pro	missense_variant	13/13	1		ENSP00000268043.4
PIF1	ENST00000333425.10	c.1866+241G>C		intron_variant		1		ENSP00000328174.6

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

GnomAD3 exomes AF: 0.00267 AC: 672 AN: 251348 Hom.: 9 AF XY: 0.00190 AC XY: 258 AN XY: 135844

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.0379

Gnomad4 AMR exome AF: 0.00168

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.00228

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

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00567

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

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;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;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.57	N;N
REVEL	Benign	0.031
Sift	Benign	0.29	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.10	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs141363784; hg19: chr15-65108532;