rs1554679825

Positions:

• chr9-94605502-TC-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The ENST00000375326.9(FBP1):​c.779del​(p.Gly260GlufsTer17) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBP1 ENST00000375326.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-94605502-TC-T is Pathogenic according to our data. Variant chr9-94605502-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 526506.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBP1	NM_000507.4	c.779del	p.Gly260GlufsTer17	frameshift_variant	6/7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2	c.779del	p.Gly260GlufsTer17	frameshift_variant	7/8		NP_001121100.1
FBP1	XM_006717005.5	c.533del	p.Gly178GlufsTer17	frameshift_variant	6/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9	c.779del	p.Gly260GlufsTer17	frameshift_variant	6/7	1	NM_000507.4	ENSP00000364475	P1
FBP1	ENST00000415431.5	c.779del	p.Gly260GlufsTer17	frameshift_variant	7/8	2		ENSP00000408025	P1
FBP1	ENST00000648117.1	c.584del	p.Gly195GlufsTer17	frameshift_variant	5/6			ENSP00000498145
FBP1	ENST00000682520.1	c.*216del		3_prime_UTR_variant, NMD_transcript_variant	6/7			ENSP00000507547

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fructose-biphosphatase deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2023

ClinVar contains an entry for this variant (Variation ID: 526506). This sequence change creates a premature translational stop signal (p.Gly260Glufs*17) in the FBP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 79 amino acid(s) of the FBP1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FBP1-related conditions. This variant disrupts a region of the FBP1 protein in which other variant(s) (p.Ser321Valfs*13) have been determined to be pathogenic (PMID: 28420223, 28776561). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1554679825; hg19: chr9-97367784;