rs185972191

Variant names:

• chr9-101435912-C-T
• rs185972191
• ENST00000648064.1:c.-10-5015G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000648064.1(ALDOB):​c.-10-5015G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00679 in 152,140 control chromosomes in the GnomAD database, including 5 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 0.0068 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDOB ENST00000648064.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:3
• Conservation: PhyloP100: 0.904
• Publications: 0 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 9-101435912-C-T is Benign according to our data. Variant chr9-101435912-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 500745.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00679 (1033/152140) while in subpopulation AMR AF = 0.00949 (145/15284). AF 95% confidence interval is 0.00881. There are 5 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000648064.1. 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.-214G>A		upstream_gene	N/A	NP_000026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	ENST00000648064.1		c.-10-5015G>A		intron	N/A	ENSP00000497990.1	P05062
	ALDOB	ENST00000648758.1		c.-10-5015G>A		intron	N/A	ENSP00000497731.1	P05062
	ALDOB	ENST00000903775.1		c.-10-5015G>A		intron	N/A	ENSP00000573834.1

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1034 AN: 152022 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0110

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 10 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 6

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.00679 AC: 1033 AN: 152140 Hom.: 5 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74398

African (AFR) AF: 0.00210 AC: 87 AN: 41500

American (AMR) AF: 0.00949 AC: 145 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4812

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 67988

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00868 Hom.: 1

Bravo AF: 0.00751

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	1	not provided (4)
1	1	1	Hereditary fructosuria (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.49
PhyloP100		0.90
PromoterAI		0.014	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs185972191; hg19: chr9-104198194;