10-6216139-C-T

Variant names:

• chr10-6216139-C-T
• NM_004566.4:c.314C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001323017.2(PFKFB3):​c.-286C>T variant causes a 5 prime UTR premature start codon gain change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PFKFB3 NM_001323017.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.91

Genes affected

PFKFB3 (HGNC:8874): (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3) The protein encoded by this gene belongs to a family of bifunctional proteins that are involved in both the synthesis and degradation of fructose-2,6-bisphosphate, a regulatory molecule that controls glycolysis in eukaryotes. The encoded protein has a 6-phosphofructo-2-kinase activity that catalyzes the synthesis of fructose-2,6-bisphosphate (F2,6BP), and a fructose-2,6-biphosphatase activity that catalyzes the degradation of F2,6BP. This protein is required for cell cycle progression and prevention of apoptosis. It functions as a regulator of cyclin-dependent kinase 1, linking glucose metabolism to cell proliferation and survival in tumor cells. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31753868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKFB3	NM_004566.4	c.314C>T	p.Ala105Val	missense_variant	Exon 4 of 15	ENST00000379775.9	NP_004557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKFB3	ENST00000379775.9	c.314C>T	p.Ala105Val	missense_variant	Exon 4 of 15	1	NM_004566.4	ENSP00000369100.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.314C>T (p.A105V) alteration is located in exon 4 (coding exon 4) of the PFKFB3 gene. This alteration results from a C to T substitution at nucleotide position 314, causing the alanine (A) at amino acid position 105 to be replaced by a valine (V). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	23
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.020	.;.;.;T;.;T;.;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;L;L;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.74	N;.;.;N;N;.;.;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.37	T;.;.;T;T;.;.;T;T;.
Sift4G	Benign	0.33	T;T;.;T;T;T;T;T;T;.
Polyphen		1.0, 0.57	.;.;.;.;.;.;.;D;P;.
Vest4		0.35
MutPred		0.50		.;.;.;Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);Gain of ubiquitination at K100 (P = 0.078);
MVP		0.64
MPC		0.50
ClinPred		0.67	D
GERP RS		5.2
Varity_R		0.30
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-6258102;