rs748629250

Variant names:

• chr15-64818037-C-A
• rs748629250
• NM_001286496.2:c.1583G>T

Your query was ambiguous. Multiple possible variants found:

• chr15-64818037-C-A
• chr15-64818037-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001286496.2(PIF1):​c.1583G>T​(p.Arg528Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R528H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PIF1 NM_001286496.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

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.1583G>T	p.Arg528Leu	missense	Exon 11 of 13	NP_001273425.1	Q9H611-1
	PIF1	NM_001286497.2		c.1583G>T	p.Arg528Leu	missense	Exon 11 of 13	NP_001273426.1	Q9H611-3
	PIF1	NM_025049.4		c.1583G>T	p.Arg528Leu	missense	Exon 11 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.1583G>T	p.Arg528Leu	missense	Exon 11 of 13	ENSP00000452792.1	Q9H611-1
	PIF1	ENST00000333425.10	TSL:1	c.1583G>T	p.Arg528Leu	missense	Exon 11 of 13	ENSP00000328174.6	Q9H611-3
	PIF1	ENST00000268043.8	TSL:1	c.1583G>T	p.Arg528Leu	missense	Exon 11 of 13	ENSP00000268043.4	Q9H611-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249196 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000470

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461480 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.0047	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.023	D
Polyphen		0.94	P
Vest4		0.79
MutPred		0.67		Gain of sheet (P = 0.039)
MVP		0.76
MPC		0.27
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.63

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

Other links and lift over

dbSNP: rs748629250; hg19: chr15-65110236;