rs8192689

Positions:

• chr9-94617761-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000507.4(FBP1):​c.426+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,590,510 control chromosomes in the GnomAD database, including 95,582 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7989 hom., cov: 32)
  • Exomes 𝑓: 0.34 (87593 hom.)
• Consequence: FBP1 NM_000507.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003523
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.387

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 9-94617761-G-A is Benign according to our data. Variant chr9-94617761-G-A is described in ClinVar as [Benign]. Clinvar id is 256320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-94617761-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBP1	NM_000507.4	c.426+7C>T		splice_region_variant, intron_variant		ENST00000375326.9
FBP1	NM_001127628.2	c.426+7C>T		splice_region_variant, intron_variant
FBP1	XM_006717005.5	c.180+7C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBP1	ENST00000375326.9	c.426+7C>T		splice_region_variant, intron_variant		1	NM_000507.4	P1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48755 AN: 151770 Hom.: 7978 Cov.: 32

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.242

Gnomad AMR AF: 0.234

Gnomad ASJ AF: 0.232

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.393

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.336 AC: 84275 AN: 250660 Hom.: 15330 AF XY: 0.341 AC XY: 46165 AN XY: 135500

Gnomad AFR exome AF: 0.280

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.239

Gnomad EAS exome AF: 0.551

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.386

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.343 AC: 492730 AN: 1438622 Hom.: 87593 Cov.: 29 AF XY: 0.344 AC XY: 246727 AN XY: 717162

Gnomad4 AFR exome AF: 0.272

Gnomad4 AMR exome AF: 0.195

Gnomad4 ASJ exome AF: 0.240

Gnomad4 EAS exome AF: 0.585

Gnomad4 SAS exome AF: 0.383

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.340

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.321 AC: 48804 AN: 151888 Hom.: 7989 Cov.: 32 AF XY: 0.322 AC XY: 23877 AN XY: 74226

Gnomad4 AFR AF: 0.285

Gnomad4 AMR AF: 0.234

Gnomad4 ASJ AF: 0.232

Gnomad4 EAS AF: 0.554

Gnomad4 SAS AF: 0.392

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.336

Gnomad4 OTH AF: 0.306

Alfa AF: 0.320 Hom.: 10383

Bravo AF: 0.306

Asia WGS AF: 0.422 AC: 1465 AN: 3478

EpiCase AF: 0.329

EpiControl AF: 0.328

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 30, 2012	- -

Fructose-biphosphatase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.5
DANN	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.028
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: rs8192689; hg19: chr9-97380043;