9-101427398-T-G

Variant names:

• chr9-101427398-T-G
• rs1929480
• NM_000035.4:c.540+84A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000035.4(ALDOB):​c.540+84A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 1,519,468 control chromosomes in the GnomAD database, including 82,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (6012 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76225 hom.)
• Consequence: ALDOB NM_000035.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.622
• Publications: 5 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: Ambry Genetics, Myriad Women’s Health, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-101427398-T-G is Benign according to our data. Variant chr9-101427398-T-G is described in ClinVar as Benign. ClinVar VariationId is 1177040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	NM_000035.4	MANE Select	c.540+84A>C		intron	N/A	NP_000026.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	ENST00000647789.2	MANE Select	c.540+84A>C		intron	N/A	ENSP00000497767.1
	ALDOB	ENST00000648064.1		c.540+84A>C		intron	N/A	ENSP00000497990.1
	ALDOB	ENST00000648758.1		c.540+84A>C		intron	N/A	ENSP00000497731.1

Frequencies

GnomAD3 genomes AF: 0.251 AC: 38204 AN: 151980 Hom.: 6013 Cov.: 32

Gnomad AFR AF: 0.0813

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.404

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.323 AC: 441825 AN: 1367370 Hom.: 76225 AF XY: 0.322 AC XY: 219739 AN XY: 682806

African (AFR) AF: 0.0716 AC: 2266 AN: 31636

American (AMR) AF: 0.180 AC: 7424 AN: 41320

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10014 AN: 25250

East Asian (EAS) AF: 0.0663 AC: 2558 AN: 38570

South Asian (SAS) AF: 0.185 AC: 15170 AN: 81858

European-Finnish (FIN) AF: 0.320 AC: 15141 AN: 47268

Middle Eastern (MID) AF: 0.342 AC: 1824 AN: 5336

European-Non Finnish (NFE) AF: 0.356 AC: 369731 AN: 1038986

Other (OTH) AF: 0.310 AC: 17697 AN: 57146

GnomAD4 genome AF: 0.251 AC: 38200 AN: 152098 Hom.: 6012 Cov.: 32 AF XY: 0.246 AC XY: 18289 AN XY: 74348

African (AFR) AF: 0.0811 AC: 3368 AN: 41510

American (AMR) AF: 0.238 AC: 3638 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.404 AC: 1400 AN: 3468

East Asian (EAS) AF: 0.0688 AC: 356 AN: 5172

South Asian (SAS) AF: 0.171 AC: 825 AN: 4824

European-Finnish (FIN) AF: 0.314 AC: 3323 AN: 10578

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.357 AC: 24255 AN: 67958

Other (OTH) AF: 0.290 AC: 612 AN: 2112

Alfa AF: 0.292 Hom.: 2469

Bravo AF: 0.241

Asia WGS AF: 0.117 AC: 407 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary fructosuria Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.6
DANN	Benign	0.46
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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: rs1929480; hg19: chr9-104189680;