10-6219659-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004566.4(PFKFB3):c.589A>G(p.Ser197Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PFKFB3 NM_004566.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PFKFB3	NM_004566.4	c.589A>G	p.Ser197Gly	missense_variant	7/15	ENST00000379775.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PFKFB3	ENST00000379775.9	c.589A>G	p.Ser197Gly	missense_variant	7/15	1	NM_004566.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 23, 2023

The c.589A>G (p.S197G) alteration is located in exon 7 (coding exon 7) of the PFKFB3 gene. This alteration results from a A to G substitution at nucleotide position 589, causing the serine (S) at amino acid position 197 to be replaced by a glycine (G). 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	0.11
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;.;D;D;D;D;D
M_CAP	Benign	0.0053	T
MetaRNN	Uncertain	0.55	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	N;.;N;N;.;.;N;N;.
REVEL	Benign	0.18
Sift	Benign	0.14	T;.;T;T;.;.;T;T;.
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T;.
Polyphen		0.29, 0.20	.;.;.;.;.;.;B;B;.
Vest4		0.66
MutPred		0.40		.;.;Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);Loss of phosphorylation at S197 (P = 0.0675);
MVP		0.72
MPC		0.53
ClinPred		0.96	D
GERP RS		5.4
Varity_R		0.39
gMVP		0.58

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: chr10-6261622;