rs757653154

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000507.4(FBP1):c.960_961insG(p.Ser321ValfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000131 in 1,613,556 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G320G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

FBP1
NM_000507.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: -0.565

Publications

11 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 links:

PCAT7 (HGNC:48824): (prostate cancer associated transcript 7)

PCAT7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PP5

Variant 9-94603437-A-AC is Pathogenic according to our data. Variant chr9-94603437-A-AC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 867.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.960_961insG	p.Ser321ValfsTer13	frameshift_variant	Exon 7 of 7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2 link	c.960_961insG	p.Ser321ValfsTer13	frameshift_variant	Exon 8 of 8		NP_001121100.1
FBP1	XM_006717005.5 link	c.714_715insG	p.Ser239ValfsTer13	frameshift_variant	Exon 7 of 7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9 link	c.960_961insG	p.Ser321ValfsTer13	frameshift_variant	Exon 7 of 7	1	NM_000507.4	ENSP00000364475.5

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151728

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000722

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000796

AC:

AN:

251240

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000122

AC:

179

AN:

1461828

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000134

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86244

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000141

AC:

157

AN:

1111974

Other (OTH)

AF:

0.0000828

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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

AF:

0.000211

AC:

AN:

151728

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74068

show subpopulations

African (AFR)

AF:

0.000315

AC:

AN:

41298

American (AMR)

AF:

0.000722

AC:

AN:

15226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4778

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67940

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000158

Hom.:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fructose-biphosphatase deficiency

Pathogenic:7

May 28, 2019

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser321Valfs*13) in the FBP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the FBP1 protein. This variant is present in population databases (rs757653154, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with fructose-1,6-bisphosphatase deficiency (PMID: 28420223, 28776561). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 867). For these reasons, this variant has been classified as Pathogenic.

Oct 01, 1997

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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:clinical testing

Jan 10, 2025

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 12, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

not provided

Pathogenic:2

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

FBP1: PVS1, PM2

Dec 13, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP4, PM2_moderate, PM3_very_strong, PS3, PVS1_moderate

Inborn genetic diseases

Pathogenic:1

Aug 01, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.960_961insG (p.S321Vfs*13) alteration, located in exon 7 (coding exon 7) of the FBP1 gene, consists of an insertion of G at position 960, causing a translational frameshift with a predicted alternate stop codon after 13 amino acids. This alteration occurs at the 3' terminus of the FBP1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 5% of the protein. However, premature stop codons are typically deleterious in nature. This alteration has been detected in the homozygous state, or in conjunction with another FBP1 disease-causing alteration, in multiple unrelated individuals with fructose-1,6-bisphosphatase deficiency (Kato, 2015; Lebigot, 2015; Ponzi, 2018; Li, 2017; Lee, 2019; Lu, 2017; Kikawa, 1997; Kikawa, 1995). Based on the available evidence, this alteration is classified as pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.56

Mutation Taster

=10/190

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over