10-6220854-C-G

Variant names:

• chr10-6220854-C-G
• rs200723320
• NM_004566.4:c.820C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004566.4(PFKFB3):​c.820C>G​(p.Arg274Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,038 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R274Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PFKFB3 NM_004566.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004566.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKFB3	NM_004566.4	MANE Select	c.820C>G	p.Arg274Gly	missense	Exon 8 of 15	NP_004557.1	Q16875-1
	PFKFB3	NM_001363545.2		c.820C>G	p.Arg274Gly	missense	Exon 8 of 15	NP_001350474.1	A0A1W2PR17
	PFKFB3	NM_001282630.3		c.862C>G	p.Arg288Gly	missense	Exon 8 of 15	NP_001269559.1	Q16875-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PFKFB3	ENST00000379775.9	TSL:1 MANE Select	c.820C>G	p.Arg274Gly	missense	Exon 8 of 15	ENSP00000369100.4	Q16875-1
	PFKFB3	ENST00000379789.8	TSL:1	c.760C>G	p.Arg254Gly	missense	Exon 8 of 15	ENSP00000369115.4	Q16875-3
	PFKFB3	ENST00000640683.1	TSL:5	c.820C>G	p.Arg274Gly	missense	Exon 8 of 15	ENSP00000492001.1	A0A1W2PR17

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459038 Hom.: 0 Cov.: 33 AF XY: 0.00000276 AC XY: 2 AN XY: 725928

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111802

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.24
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.92	P
Vest4		0.68
MutPred		0.54		Loss of stability (P = 0.0076)
MVP		0.78
MPC		1.4
ClinPred		0.99	D
GERP RS		-1.1
Varity_R		0.72
gMVP		0.78
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs200723320; hg19: chr10-6262817;