9-94617839-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_000507.4(FBP1):c.355G>A(p.Asp119Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D119E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

FBP1
NM_000507.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 6.07

Publications

4 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: Pathogenic. The variant received 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-94617837-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 624361.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 9-94617839-C-T is Pathogenic according to our data. Variant chr9-94617839-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 214364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
FBP1	NM_000507.4 link	c.355G>A	p.Asp119Asn	missense_variant	Exon 3 of 7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2 link	c.355G>A	p.Asp119Asn	missense_variant	Exon 4 of 8		NP_001121100.1
FBP1	XM_006717005.5 link	c.109G>A	p.Asp37Asn	missense_variant	Exon 3 of 7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9 link	c.355G>A	p.Asp119Asn	missense_variant	Exon 3 of 7	1	NM_000507.4	ENSP00000364475.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000199

AC:

AN:

251346

AF XY:

0.0000368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461200

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.000101

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111464

Other (OTH)

AF:

0.0000166

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.0000101

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fructose-biphosphatase deficiency

Pathogenic:2

Mar 27, 2017

Department of Medical Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:in vitro

Dec 21, 2022

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1

Jul 15, 2014

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp119Asn (GAT>AAT): c.355 G>A in exon 3 of the FBP1 gene (NM_000507.3). It has not been reported as a benign polymorphism to our knowledge. It has been presented as a mutation in association with fructose 1,6-bisphosphatase deficiency in a poster session (Frisso et al., 2013). The D119N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MITONUC-MITOP panel(s).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

LIST_S2

Benign

0.0

.;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;H;.

PhyloP100

6.1

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-4.8

D;D;D

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0050

D;D;D

Vest4

0.94

ClinPred

1.0

GERP RS

5.1

Varity_R

0.96

gMVP

0.98

Mutation Taster

=56/44

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over