10-3101404-C-T

Variant names:

• chr10-3101404-C-T
• rs138939047
• NM_002627.5:c.304C>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001323069.2(PFKP):​c.-199C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,602,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: PFKP NM_001323069.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

PFKP (HGNC:8878): (phosphofructokinase, platelet) This gene encodes a member of the phosphofructokinase A protein family. The encoded enzyme is the platelet-specific isoform of phosphofructokinase and plays a key role in glycolysis regulation. This gene may play a role in metabolic reprogramming in some cancers, including clear cell renal cell carcinomas, and cancer of the bladder, breast, and lung. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKP	NM_002627.5	c.304C>T	p.Arg102Cys	missense_variant	Exon 4 of 22	ENST00000381125.9	NP_002618.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKP	ENST00000381125.9	c.304C>T	p.Arg102Cys	missense_variant	Exon 4 of 22	1	NM_002627.5	ENSP00000370517.4

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000973 AC: 22 AN: 226082 Hom.: 0 AF XY: 0.0000732 AC XY: 9 AN XY: 122954

Gnomad AFR exome AF: 0.0000729

Gnomad AMR exome AF: 0.0000924

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000119

Gnomad SAS exome AF: 0.0000704

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000139

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000483 AC: 70 AN: 1449816 Hom.: 0 Cov.: 31 AF XY: 0.0000472 AC XY: 34 AN XY: 720330

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.000139

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000593

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.0000443

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152318 Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000279 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.000157 AC: 19

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.304C>T (p.R102C) alteration is located in exon 4 (coding exon 4) of the PFKP gene. This alteration results from a C to T substitution at nucleotide position 304, causing the arginine (R) at amino acid position 102 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	3.9	.;H;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.3	.;D;D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0030	.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.78, 0.80
MVP		0.79
MPC		0.83
ClinPred		0.97	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.89

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: rs138939047; hg19: chr10-3143596;