rs757653154

Positions:

chr9-94603437-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000507.4(FBP1):c.960_961insG(p.Ser321fs) 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:8

Conservation

PhyloP100: -0.565

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:):

PCAT7 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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. Fraction of 0.056 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-94603437-A-AC is Pathogenic according to our data. Variant chr9-94603437-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBP1	NM_000507.4 linkuse as main transcript	c.960_961insG	p.Ser321fs	frameshift_variant	7/7	ENST00000375326.9	NP_000498.2	P09467
FBP1	NM_001127628.2 linkuse as main transcript	c.960_961insG	p.Ser321fs	frameshift_variant	8/8		NP_001121100.1	P09467Q2TU34
FBP1	XM_006717005.5 linkuse as main transcript	c.714_715insG	p.Ser239fs	frameshift_variant	7/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9 linkuse as main transcript	c.960_961insG	p.Ser321fs	frameshift_variant	7/7	1	NM_000507.4	ENSP00000364475.5		P09467

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

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251240

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135798

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 SAS exome

AF:

0.0000654

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

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000141

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000211

AC:

AN:

151728

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

AN XY:

74068

show subpopulations

Gnomad4 AFR

AF:

0.000315

Gnomad4 AMR

AF:

0.000722

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000158

Hom.:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fructose-biphosphatase deficiency

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine	Mar 27, 2017	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1997	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Molecular Medicine, Children’s Hospital of Fudan University	Dec 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	FBP1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 13, 2023	PP4, PM2_moderate, PM3_very_strong, PS3, PVS1_moderate -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2022

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over