9-94606867-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000507.4(FBP1):c.653G>A(p.Arg218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.94 in 1,613,876 control chromosomes in the GnomAD database, including 713,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar.

Frequency

Genomes: 𝑓 0.96 ( 70164 hom., cov: 33)

Exomes 𝑓: 0.94 ( 643734 hom. )

Consequence

FBP1
NM_000507.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.154

Publications

45 publications found

Variant links:

Genes affected

FBP1 (HGNC:3606): (fructose-bisphosphatase 1) Fructose-1,6-bisphosphatase 1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. Fructose-1,6-diphosphatase deficiency is associated with hypoglycemia and metabolic acidosis. [provided by RefSeq, Jul 2008]

FBP1 Gene-Disease associations (from GenCC):

fructose-1,6-bisphosphatase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp, Orphanet

FBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000507.4

BP4

Computational evidence support a benign effect (MetaRNN=5.689069E-7).

BP6

Variant 9-94606867-C-T is Benign according to our data. Variant chr9-94606867-C-T is described in ClinVar as Benign. ClinVar VariationId is 256323.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.979 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000507.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBP1	NM_000507.4	MANE Select	c.653G>A	p.Arg218Lys	missense	Exon 5 of 7	NP_000498.2
	FBP1	NM_001127628.2		c.653G>A	p.Arg218Lys	missense	Exon 6 of 8	NP_001121100.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FBP1	ENST00000375326.9	TSL:1 MANE Select	c.653G>A	p.Arg218Lys	missense	Exon 5 of 7	ENSP00000364475.5
FBP1	ENST00000884868.1		c.653G>A	p.Arg218Lys	missense	Exon 6 of 8	ENSP00000554927.1
FBP1	ENST00000945615.1		c.653G>A	p.Arg218Lys	missense	Exon 5 of 7	ENSP00000615674.1

Frequencies

GnomAD3 genomes

AF:

0.960

AC:

146064

AN:

152202

Hom.:

70103

Cov.:

show subpopulations

Gnomad AFR

AF:

0.987

Gnomad AMI

AF:

0.956

Gnomad AMR

AF:

0.973

Gnomad ASJ

AF:

0.964

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.960

Gnomad FIN

AF:

0.943

Gnomad MID

AF:

0.972

Gnomad NFE

AF:

0.939

Gnomad OTH

AF:

0.961

GnomAD2 exomes

AF:

0.956

AC:

240380

AN:

251358

AF XY:

0.955

show subpopulations

Gnomad AFR exome

AF:

0.986

Gnomad AMR exome

AF:

0.980

Gnomad ASJ exome

AF:

0.962

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.945

Gnomad NFE exome

AF:

0.940

Gnomad OTH exome

AF:

0.953

GnomAD4 exome

AF:

0.938

AC:

1371406

AN:

1461556

Hom.:

643734

Cov.:

AF XY:

0.939

AC XY:

682622

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.987

AC:

33046

AN:

33470

American (AMR)

AF:

0.978

AC:

43745

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.959

AC:

25065

AN:

26128

East Asian (EAS)

AF:

1.00

AC:

39687

AN:

39698

South Asian (SAS)

AF:

0.953

AC:

82190

AN:

86252

European-Finnish (FIN)

AF:

0.945

AC:

50455

AN:

53416

Middle Eastern (MID)

AF:

0.952

AC:

5482

AN:

5756

European-Non Finnish (NFE)

AF:

0.931

AC:

1034655

AN:

1111742

Other (OTH)

AF:

0.945

AC:

57081

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4437

8874

13310

17747

22184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21554

43108

64662

86216

107770

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.960

AC:

146184

AN:

152320

Hom.:

70164

Cov.:

AF XY:

0.960

AC XY:

71501

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.987

AC:

41042

AN:

41594

American (AMR)

AF:

0.973

AC:

14898

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.964

AC:

3348

AN:

3472

East Asian (EAS)

AF:

0.999

AC:

5171

AN:

5174

South Asian (SAS)

AF:

0.960

AC:

4621

AN:

4816

European-Finnish (FIN)

AF:

0.943

AC:

10006

AN:

10606

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.939

AC:

63907

AN:

68030

Other (OTH)

AF:

0.961

AC:

2034

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

307

614

920

1227

1534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.946

Hom.:

230735

Bravo

AF:

0.962

TwinsUK

AF:

0.927

AC:

3436

ALSPAC

AF:

0.926

AC:

3567

ESP6500AA

AF:

0.983

AC:

4330

ESP6500EA

AF:

0.940

AC:

8083

ExAC

AF:

0.956

AC:

116075

Asia WGS

AF:

0.977

AC:

3393

AN:

3478

EpiCase

AF:

0.939

EpiControl

AF:

0.938

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fructose-biphosphatase deficiency (3)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.10

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.32

MetaRNN

Benign

5.7e-7

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.16

PhyloP100

0.15

PrimateAI

Benign

0.31

PROVEAN

Benign

0.81

REVEL

Benign

0.083

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.026

MPC

0.30

ClinPred

0.0052

GERP RS

1.6

Varity_R

0.29

gMVP

0.50

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over