chr9-94603413-G-T

Position:

• chr9-94603413-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000507.4(FBP1):​c.985C>A​(p.Leu329Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FBP1 NM_000507.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.324

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]

PCAT7 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1627563).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBP1	NM_000507.4	c.985C>A	p.Leu329Met	missense_variant	7/7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2	c.985C>A	p.Leu329Met	missense_variant	8/8		NP_001121100.1
FBP1	XM_006717005.5	c.739C>A	p.Leu247Met	missense_variant	7/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326.9	c.985C>A	p.Leu329Met	missense_variant	7/7	1	NM_000507.4	ENSP00000364475.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fructose-biphosphatase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2022

This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 329 of the FBP1 protein (p.Leu329Met). 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. 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 not expected to disrupt FBP1 protein function. This variant disrupts the p.Leu329 amino acid residue in FBP1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25601412, 29016355, 29774539, 30858132). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.18	.;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.68	T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	.;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.93	.;N;N
REVEL	Benign	0.086
Sift	Benign	0.17	.;T;T
Sift4G	Benign	0.23	.;T;T
Polyphen		0.078	.;B;B
Vest4		0.22, 0.22
MutPred		0.47		.;Loss of stability (P = 0.0486);Loss of stability (P = 0.0486);
MVP		0.59
MPC		0.30
ClinPred		0.21	T
GERP RS		1.3
Varity_R		0.22
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-97365695;