9-94603260-A-C

Position:

• chr9-94603260-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000507.4(FBP1):​c.*121T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 833,908 control chromosomes in the GnomAD database, including 187 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 0.013 (25 hom., cov: 33)
  • Exomes 𝑓: 0.018 (162 hom.)
• Consequence: FBP1 NM_000507.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.254

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-94603260-A-C is Benign according to our data. Variant chr9-94603260-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 913848.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0132 (2009/152300) while in subpopulation SAS AF= 0.0296 (143/4824). AF 95% confidence interval is 0.0257. There are 25 homozygotes in gnomad4. There are 997 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBP1	NM_000507.4	c.*121T>G		3_prime_UTR_variant	7/7	ENST00000375326.9	NP_000498.2
FBP1	NM_001127628.2	c.*121T>G		3_prime_UTR_variant	8/8		NP_001121100.1
FBP1	XM_006717005.5	c.*121T>G		3_prime_UTR_variant	7/7		XP_006717068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBP1	ENST00000375326	c.*121T>G		3_prime_UTR_variant	7/7	1	NM_000507.4	ENSP00000364475.5

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2011 AN: 152182 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0115

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.0302

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0158

Gnomad OTH AF: 0.0187

GnomAD4 exome AF: 0.0181 AC: 12349 AN: 681608 Hom.: 162 Cov.: 9 AF XY: 0.0189 AC XY: 6789 AN XY: 360002

Gnomad4 AFR exome AF: 0.00363

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.0614

Gnomad4 EAS exome AF: 0.0391

Gnomad4 SAS exome AF: 0.0275

Gnomad4 FIN exome AF: 0.00551

Gnomad4 NFE exome AF: 0.0156

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0132 AC: 2009 AN: 152300 Hom.: 25 Cov.: 33 AF XY: 0.0134 AC XY: 997 AN XY: 74470

Gnomad4 AFR AF: 0.00344

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.0296

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0158

Gnomad4 OTH AF: 0.0185

Alfa AF: 0.0163 Hom.: 8

Bravo AF: 0.0125

Asia WGS AF: 0.0250 AC: 86 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fructose-biphosphatase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.52

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: rs2274689; hg19: chr9-97365542;