rs142431256

Variant names:

• chr9-101421541-A-G
• rs142431256
• NM_000035.4:c.*268T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000035.4(ALDOB):​c.*268T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00726 in 503,614 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0063 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (15 hom.)
• Consequence: ALDOB NM_000035.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.29
• Publications: 1 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Myriad Women’s Health
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00629 (957/152260) while in subpopulation NFE AF = 0.0105 (713/68008). AF 95% confidence interval is 0.00985. There are 10 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.*268T>C		3_prime_UTR	Exon 9 of 9	NP_000026.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	ENST00000647789.2	MANE Select	c.*268T>C		3_prime_UTR	Exon 9 of 9	ENSP00000497767.1	P05062
	ALDOB	ENST00000648064.1		c.*268T>C		3_prime_UTR	Exon 9 of 9	ENSP00000497990.1	P05062
	ALDOB	ENST00000903775.1		c.*268T>C		3_prime_UTR	Exon 10 of 10	ENSP00000573834.1

Frequencies

GnomAD3 genomes AF: 0.00628 AC: 956 AN: 152142 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00768 AC: 2698 AN: 351354 Hom.: 15 Cov.: 0 AF XY: 0.00749 AC XY: 1416 AN XY: 188974

African (AFR) AF: 0.00236 AC: 24 AN: 10162

American (AMR) AF: 0.00599 AC: 100 AN: 16690

Ashkenazi Jewish (ASJ) AF: 0.00219 AC: 23 AN: 10494

East Asian (EAS) AF: 0.00 AC: 0 AN: 20850

South Asian (SAS) AF: 0.00497 AC: 223 AN: 44886

European-Finnish (FIN) AF: 0.00156 AC: 29 AN: 18586

Middle Eastern (MID) AF: 0.000681 AC: 1 AN: 1468

European-Non Finnish (NFE) AF: 0.0103 AC: 2149 AN: 208642

Other (OTH) AF: 0.00761 AC: 149 AN: 19576

GnomAD4 genome AF: 0.00629 AC: 957 AN: 152260 Hom.: 10 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74456

African (AFR) AF: 0.00200 AC: 83 AN: 41560

American (AMR) AF: 0.00601 AC: 92 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4824

European-Finnish (FIN) AF: 0.00208 AC: 22 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 68008

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00709 Hom.: 2

Bravo AF: 0.00656

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary fructosuria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.046
DANN	Benign	0.80
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

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: rs142431256; hg19: chr9-104183823;