rs201591116

chr9-94620425-G-Achr9-94620425-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000507.4(FBP1):c.237C>T(p.Asn79=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,158 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (24 hom.)
• Consequence: FBP1 NM_000507.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.921

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 9-94620425-G-A is Benign according to our data. Variant chr9-94620425-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 137363.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBP1	NM_000507.4	c.237C>T	p.Asn79=	synonymous_variant	2/7	ENST00000375326.9
FBP1	NM_001127628.2	c.237C>T	p.Asn79=	synonymous_variant	3/8
FBP1	XM_006717005.5	c.-10C>T		5_prime_UTR_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBP1	ENST00000375326.9	c.237C>T	p.Asn79=	synonymous_variant	2/7	1	NM_000507.4	P1

Frequencies

GnomAD3 genomes AF: 0.00191 AC: 290 AN: 152178 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00558

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.0196

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00262 AC: 658 AN: 251476 Hom.: 12 AF XY: 0.00248 AC XY: 337 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00386

Gnomad SAS exome AF: 0.000947

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00116 AC: 1700 AN: 1461862 Hom.: 24 Cov.: 32 AF XY: 0.00115 AC XY: 839 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00194

Gnomad4 SAS exome AF: 0.00104

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00190 AC: 290 AN: 152296 Hom.: 6 Cov.: 32 AF XY: 0.00257 AC XY: 191 AN XY: 74462

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00559

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.0196

Gnomad4 NFE AF: 0.000529

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000549 Hom.: 1

Bravo AF: 0.000242

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fructose-biphosphatase deficiency Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 17, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	8.9
Dann	Benign	0.70

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: rs201591116; hg19: chr9-97382707; COSMIC: COSV64689325;