rs121918191

Positions:

• chr9-94606939-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The ENST00000375326.9(FBP1):​c.581T>C​(p.Phe194Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBP1 ENST00000375326.9 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 9-94606939-A-G is Pathogenic according to our data. Variant chr9-94606939-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 871.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBP1	NM_000507.4	c.581T>C	p.Phe194Ser	missense_variant	5/7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2	c.581T>C	p.Phe194Ser	missense_variant	6/8		NP_001121100.1
FBP1	XM_006717005.5	c.335T>C	p.Phe112Ser	missense_variant	5/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9	c.581T>C	p.Phe194Ser	missense_variant	5/7	1	NM_000507.4	ENSP00000364475	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fructose-biphosphatase deficiency Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	1.0	D;.;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.4	.;H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.9	.;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.94, 0.94
MutPred		0.91		.;Loss of stability (P = 0.0386);Loss of stability (P = 0.0386);.;
MVP		0.98
MPC		1.4
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.98

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: rs121918191; hg19: chr9-97369221;