rs141888548

Positions:

• chr9-101425447-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_000035.4(ALDOB):​c.799+6G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00327 in 1,614,048 control chromosomes in the GnomAD database, including 12 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 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (12 hom.)
• Consequence: ALDOB NM_000035.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.0002405
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -1.29

Genes affected

ALDOB (HGNC:417): (aldolase, fructose-bisphosphate B) Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a tetrameric glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates have 3 aldolase isozymes which are distinguished by their electrophoretic and catalytic properties. Differences indicate that aldolases A, B, and C are distinct proteins, the products of a family of related 'housekeeping' genes exhibiting developmentally regulated expression of the different isozymes. The developing embryo produces aldolase A, which is produced in even greater amounts in adult muscle where it can be as much as 5% of total cellular protein. In adult liver, kidney and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. There is a high degree of homology between aldolase A and C. Defects in ALDOB cause hereditary fructose intolerance. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-101425447-C-T is Benign according to our data. Variant chr9-101425447-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDOB	NM_000035.4	c.799+6G>A		splice_donor_region_variant, intron_variant		ENST00000647789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDOB	ENST00000647789.2	c.799+6G>A		splice_donor_region_variant, intron_variant			NM_000035.4	P1
ALDOB	ENST00000648064.1	c.799+6G>A		splice_donor_region_variant, intron_variant				P1
ALDOB	ENST00000648758.1	c.799+6G>A		splice_donor_region_variant, intron_variant				P1
ALDOB	ENST00000649902.1	c.799+6G>A		splice_donor_region_variant, intron_variant

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 370 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00201 AC: 506 AN: 251322 Hom.: 1 AF XY: 0.00206 AC XY: 280 AN XY: 135846

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00336 AC: 4913 AN: 1461796 Hom.: 12 Cov.: 32 AF XY: 0.00332 AC XY: 2417 AN XY: 727202

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00957

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.00298

GnomAD4 genome AF: 0.00243 AC: 370 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74430

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00354 Hom.: 0

Bravo AF: 0.00249

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00350

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2022	- -

Hereditary fructosuria Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 18, 2019	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ALDOB: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 25, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.7
DANN	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.0080
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: rs141888548; hg19: chr9-104187729;