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GeneBe

10-6221644-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004566.4(PFKFB3):c.982G>A(p.Val328Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,610,574 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

PFKFB3
NM_004566.4 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04387334).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PFKFB3NM_004566.4 linkuse as main transcriptc.982G>A p.Val328Ile missense_variant 10/15 ENST00000379775.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PFKFB3ENST00000379775.9 linkuse as main transcriptc.982G>A p.Val328Ile missense_variant 10/151 NM_004566.4 Q16875-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152184
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00165
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000195
AC:
47
AN:
241642
Hom.:
0
AF XY:
0.000321
AC XY:
42
AN XY:
130794
show subpopulations
Gnomad AFR exome
AF:
0.000130
Gnomad AMR exome
AF:
0.0000298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00125
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000550
Gnomad OTH exome
AF:
0.000171
GnomAD4 exome
AF:
0.000115
AC:
167
AN:
1458272
Hom.:
2
Cov.:
32
AF XY:
0.000152
AC XY:
110
AN XY:
725184
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.0000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00115
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000153
Gnomad4 OTH exome
AF:
0.000166
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152302
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00166
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000999
Hom.:
0
Bravo
AF:
0.0000756
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000165
AC:
20

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 17, 2022The c.982G>A (p.V328I) alteration is located in exon 10 (coding exon 10) of the PFKFB3 gene. This alteration results from a G to A substitution at nucleotide position 982, causing the valine (V) at amino acid position 328 to be replaced by an isoleucine (I). 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
0.074
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.32
Cadd
Uncertain
24
Dann
Uncertain
0.99
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.14
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D;.;D;D;D;D;D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.044
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.83
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.48
N;.;N;N;.;.;N;N;.
REVEL
Benign
0.091
Sift
Benign
0.22
T;.;T;T;.;.;T;T;.
Sift4G
Benign
0.36
T;T;T;T;T;T;T;T;.
Polyphen
0.74, 0.10
.;.;.;.;.;.;P;B;.
Vest4
0.48
MVP
0.74
MPC
0.56
ClinPred
0.042
T
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.20
gMVP
0.37

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371075114; hg19: chr10-6263607; API