rs780803192

Positions:

• chr9-94605504-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000507.4(FBP1):​c.778G>A​(p.Gly260Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FBP1 NM_000507.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 9-94605504-C-T is Pathogenic according to our data. Variant chr9-94605504-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 561989.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	c.778G>A	p.Gly260Arg	missense_variant	6/7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2	c.778G>A	p.Gly260Arg	missense_variant	7/8		NP_001121100.1
FBP1	XM_006717005.5	c.532G>A	p.Gly178Arg	missense_variant	6/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9	c.778G>A	p.Gly260Arg	missense_variant	6/7	1	NM_000507.4	ENSP00000364475.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251356 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fructose-biphosphatase deficiency Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 09, 2024	Variant summary: FBP1 c.778G>A (p.Gly260Arg) results in a non-conservative amino acid change located in the Fructose-1-6-bisphosphatase class 1, C-terminal domain (IPR044015) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251356 control chromosomes. c.778G>A has been reported in the literature in homozygous individuals affected with Fructose-biphosphatase deficiency (e.g. Herzog_1999, Bhai_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in undetectable fructose-1,6-bisphosphatase activity in transfected COS-1 cells (Herzog_1999). The following publications have been ascertained in the context of this evaluation (PMID: 29774539, 33083013, 10234608). ClinVar contains an entry for this variant (Variation ID: 561989). Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.778G>A in Exon 6 of the FBP1 gene that results in the amino acid substitution p.Gly260Arg was identified. The observed variant has a minor allele frequency of 0.00001% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 561989 as of 2020-07-25). The same variant has been previously documented in patients affected with Fructose-1, 6 Bisphosphatase Deficiency (Yasir Zahoor, Muhammad et al., 2020). Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital	Jul 12, 2014	- -
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	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 17, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FBP1 function (PMID: 10234608). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FBP1 protein function. ClinVar contains an entry for this variant (Variation ID: 561989). This variant is also known as G-to-A transition at position G778 in exon 6; G261A. This missense change has been observed in individual(s) with fructose-1,6-bisphosphatase deficiency (PMID: 10234608, 20151204). This variant is present in population databases (rs780803192, gnomAD 0.006%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 260 of the FBP1 protein (p.Gly260Arg). -

FBP1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 09, 2023

The FBP1 c.778G>A variant is predicted to result in the amino acid substitution p.Gly260Arg. This variant has been reported in the compound heterozygous and homozygous state in multiple individuals with features consistent with fructose-1,6-bisphosphatase deficiency (see for example, Table 1, Moey et al. 2017. PubMed ID: 29203193; Figure 2, Yasir Zahoor et al. 2019. PubMed ID: 31584309; Table 1, Gorce et al. 2021. PubMed ID: 34687058). In at least one patient, clinical and biochemical findings were consistent with the disease (Patient 3, Moey et al. 2017. PubMed ID: 29203193). In vitro functional characterization showed that this variant leads to undetectable enzyme levels (Herzog et al. 1999. PubMed ID: 10234608). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-97367786-C-T). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	.;H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.1	.;D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	.;D;D
Polyphen		1.0	.;D;D
Vest4		1.0
MutPred		0.97		.;Gain of MoRF binding (P = 0.0268);Gain of MoRF binding (P = 0.0268);
MVP		0.97
MPC		1.1
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.85

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

Other links and lift over

dbSNP: rs780803192; hg19: chr9-97367786;