NM_004566.4:c.907A>G

Variant names:

• chr10-6221456-A-G
• rs769974312
• NM_004566.4:c.907A>G

Variant summary

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

The NM_004566.4(PFKFB3):​c.907A>G​(p.Ser303Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. S303C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PFKFB3 NM_004566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33

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=0.37137794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PFKFB3	NM_004566.4	c.907A>G	p.Ser303Gly	missense_variant	Exon 9 of 15	ENST00000379775.9	NP_004557.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PFKFB3	ENST00000379775.9	c.907A>G	p.Ser303Gly	missense_variant	Exon 9 of 15	1	NM_004566.4	ENSP00000369100.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	.;.;T;.;T;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.83	T;T;T;.;T;T;T;T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	-0.69	.;.;.;.;.;.;N;N;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;.;N;N;.;.;N;N;.
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;.;D;D;.;.;D;D;.
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;.
Polyphen		0.0060, 0.0030	.;.;.;.;.;.;B;B;.
Vest4		0.25
MutPred		0.80		.;.;Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);Gain of catalytic residue at S303 (P = 0.013);
MVP		0.73
MPC		0.42
ClinPred		0.63	D
GERP RS		3.3
Varity_R		0.66
gMVP		0.81

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: rs769974312; hg19: chr10-6263419;