9-101421603-G-T

Position:

• chr9-101421603-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000035.4(ALDOB):​c.*206C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0886 in 633,154 control chromosomes in the GnomAD database, including 2,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.074 (525 hom., cov: 32)
  • Exomes 𝑓: 0.093 (2436 hom.)
• Consequence: ALDOB NM_000035.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.341

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-101421603-G-T is Benign according to our data. Variant chr9-101421603-G-T is described in ClinVar as [Benign]. Clinvar id is 364303.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDOB	NM_000035.4	c.*206C>A		3_prime_UTR_variant	9/9	ENST00000647789.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDOB	ENST00000647789.2	c.*206C>A		3_prime_UTR_variant	9/9		NM_000035.4	P1
ALDOB	ENST00000648064.1	c.*206C>A		3_prime_UTR_variant	9/9			P1
ALDOB	ENST00000648758.1			downstream_gene_variant				P1

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11299 AN: 152144 Hom.: 525 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.0842

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.0643

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0875

GnomAD4 exome AF: 0.0932 AC: 44822 AN: 480892 Hom.: 2436 Cov.: 4 AF XY: 0.0950 AC XY: 24363 AN XY: 256322

Gnomad4 AFR exome AF: 0.0201

Gnomad4 AMR exome AF: 0.0593

Gnomad4 ASJ exome AF: 0.0853

Gnomad4 EAS exome AF: 0.00287

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.0717

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.0919

GnomAD4 genome AF: 0.0742 AC: 11294 AN: 152262 Hom.: 525 Cov.: 32 AF XY: 0.0736 AC XY: 5477 AN XY: 74450

Gnomad4 AFR AF: 0.0192

Gnomad4 AMR AF: 0.0746

Gnomad4 ASJ AF: 0.0842

Gnomad4 EAS AF: 0.00366

Gnomad4 SAS AF: 0.0987

Gnomad4 FIN AF: 0.0643

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.0866

Alfa AF: 0.105 Hom.: 932

Bravo AF: 0.0720

Asia WGS AF: 0.0460 AC: 161 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary fructosuria Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.62

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: rs17772869; hg19: chr9-104183885;