10-6221494-C-T

Variant names:

• chr10-6221494-C-T
• rs34184265
• NM_004566.4:c.945C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004566.4(PFKFB3):​c.945C>T​(p.Tyr315Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,466 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (42 hom.)
• Consequence: PFKFB3 NM_004566.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 1 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 10-6221494-C-T is Benign according to our data. Variant chr10-6221494-C-T is described in ClinVar as Benign. ClinVar VariationId is 769766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.09 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00292 (445/152326) while in subpopulation EAS AF = 0.0193 (100/5184). AF 95% confidence interval is 0.0162. There are 2 homozygotes in GnomAd4. There are 258 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.945C>T	p.Tyr315Tyr	synonymous	Exon 9 of 15	NP_004557.1	Q16875-1
	PFKFB3	NM_001363545.2		c.945C>T	p.Tyr315Tyr	synonymous	Exon 9 of 15	NP_001350474.1	A0A1W2PR17
	PFKFB3	NM_001282630.3		c.987C>T	p.Tyr329Tyr	synonymous	Exon 9 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.945C>T	p.Tyr315Tyr	synonymous	Exon 9 of 15	ENSP00000369100.4	Q16875-1
	PFKFB3	ENST00000379789.8	TSL:1	c.885C>T	p.Tyr295Tyr	synonymous	Exon 9 of 15	ENSP00000369115.4	Q16875-3
	PFKFB3	ENST00000640683.1	TSL:5	c.945C>T	p.Tyr315Tyr	synonymous	Exon 9 of 15	ENSP00000492001.1	A0A1W2PR17

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 445 AN: 152208 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00746 AC: 1863 AN: 249774 AF XY: 0.00570

Gnomad AFR exome AF: 0.00218

Gnomad AMR exome AF: 0.0390

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0150

Gnomad FIN exome AF: 0.00699

Gnomad NFE exome AF: 0.000204

Gnomad OTH exome AF: 0.00426

GnomAD4 exome AF: 0.00182 AC: 2660 AN: 1461140 Hom.: 42 Cov.: 33 AF XY: 0.00155 AC XY: 1125 AN XY: 726876

African (AFR) AF: 0.00179 AC: 60 AN: 33480

American (AMR) AF: 0.0346 AC: 1548 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0139 AC: 550 AN: 39700

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86254

European-Finnish (FIN) AF: 0.00588 AC: 310 AN: 52726

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000728 AC: 81 AN: 1111988

Other (OTH) AF: 0.00157 AC: 95 AN: 60390

GnomAD4 genome AF: 0.00292 AC: 445 AN: 152326 Hom.: 2 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74484

African (AFR) AF: 0.00168 AC: 70 AN: 41574

American (AMR) AF: 0.0109 AC: 167 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.000719 Hom.: 0

Bravo AF: 0.00414

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.60
DANN	Benign	0.59
PhyloP100		-1.1
PromoterAI		-0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=85/15	polymorphism

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: rs34184265; hg19: chr10-6263457;