rs1800546

Variant names:

• chr9-101427574-C-G
• rs1800546
• NM_000035.4:c.448G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-101427574-C-G
• chr9-101427574-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 13P and 2B. PS3 PP3 PP5_Very_Strong BP4 BS2_Supporting

The NM_000035.4(ALDOB):​c.448G>C​(p.Ala150Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00439 in 1,614,172 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000476066: in vitro functional studies of ALDOB variants demonstrated that the p.Ala150Pro variant protein was highly unstable with no detectable residual enzyme activity (Esposito et al. 2002)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. A150A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (16 hom.)
• Consequence: ALDOB NM_000035.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:43 O:2
• Conservation: PhyloP100: 4.33
• Publications: 57 publications found

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]

ALDOB Gene-Disease associations (from GenCC):

• hereditary fructose intolerance

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000476066: in vitro functional studies of ALDOB variants demonstrated that the p.Ala150Pro variant protein was highly unstable with no detectable residual enzyme activity (Esposito et al. 2002).; SCV000711745: "In vitro functional studies also provide evidence that the p.Ala150Pro variant impacts protein function (Esposito 2002 PMID: 12417303, Malay 2002 PMID: 12464284, Malay 2005 PMID: 15733923)."; SCV000752027: Experimental studies have shown that this missense change affects ALDOB function (PMID: 12417303, 12464284).; SCV000803454: Well-established functional studies show a deleterious effect. Severe reduction of aldolase activity towards fructose-1-phosphate (F-1-P) and fructose-1,6-bisphosphate (F-1,6-P2) measured in hepatic biopsies. In vitro expression studies confirm that the recombinant enzyme has defective activity (PMID:12417303) (PMID:12205126).; SCV002767902: "In vitro assays demonstrate that this missense variant results in the complete loss of catalytic activity and efficiency of substrates fructose-1,6-bisphosphate and fructose-1-phosphate." PMID:12417303; SCV004046147: Functional studies show this variant reduces substrate affinity as well as enzyme thermal stability, quaternary structure, and activity (PMID:12417303, 12464284, 15733923).; SCV004563889: Functional studies demonstrate that this variant causes protein instability and loss of enzymatic activity (Esposito 2002, Malay 2002, Malay 2005). PMID: 12464284. PMID: 12464284. PMID: 15733923.; SCV006585499: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12417303, 12464284).; SCV000322438: Published functional studies demonstrate A150P decreases substrate affinity and enzyme stability and results in loss of thermostability and significantly lower activity than wild type protein (Esposito et al., 2002; Malay et al., 2002); SCV002064384: "In vitro functional analyses showed that the p.Ala150Pro substitution has an impact on both substrate affinity and enzyme stability and wild type protein activity is reduced." PMID:12417303, PMID:12464284; SCV004885753: "In vitro functional studies show that protein with the p.A150P mutation demonstrates temperature-dependent structural changes and decreased enzyme activity compared to wild type protein (Esposito, 2002; Malay, 2002)."
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• PP5: Variant 9-101427574-C-G is Pathogenic according to our data. Variant chr9-101427574-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.021924257). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000035.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	NM_000035.4	MANE Select	c.448G>C	p.Ala150Pro	missense	Exon 5 of 9	NP_000026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	ENST00000647789.2	MANE Select	c.448G>C	p.Ala150Pro	missense	Exon 5 of 9	ENSP00000497767.1	P05062
	ALDOB	ENST00000648064.1		c.448G>C	p.Ala150Pro	missense	Exon 5 of 9	ENSP00000497990.1	P05062
	ALDOB	ENST00000648758.1		c.448G>C	p.Ala150Pro	missense	Exon 5 of 9	ENSP00000497731.1	P05062

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 476 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00534

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00295 AC: 742 AN: 251126 AF XY: 0.00299

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00435

Gnomad NFE exome AF: 0.00469

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00452 AC: 6611 AN: 1461884 Hom.: 16 Cov.: 32 AF XY: 0.00434 AC XY: 3159 AN XY: 727246

African (AFR) AF: 0.000866 AC: 29 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 51 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86258

European-Finnish (FIN) AF: 0.00479 AC: 256 AN: 53412

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00530 AC: 5892 AN: 1112010

Other (OTH) AF: 0.00427 AC: 258 AN: 60396

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74474

African (AFR) AF: 0.000938 AC: 39 AN: 41568

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00534 AC: 363 AN: 68016

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00398 Hom.: 0

Bravo AF: 0.00255

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00270 AC: 328

EpiCase AF: 0.00447

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
29	-	-	Hereditary fructosuria (31)
11	-	-	not provided (11)
1	-	-	ALDOB-related disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.3
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.93
MPC		0.13
ClinPred		0.045	T
GERP RS		6.2
Varity_R		0.94
gMVP		0.84
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1800546; hg19: chr9-104189856;