9-101430914-G-A

Variant names:

• chr9-101430914-G-A
• rs182858853
• NM_000035.4:c.-10-17C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BS2_Supporting

The NM_000035.4(ALDOB):​c.-10-17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,556,002 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: ALDOB NM_000035.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.526
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-101430914-G-A is Benign according to our data. Variant chr9-101430914-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 254729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDOB	NM_000035.4	MANE Select	c.-10-17C>T		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.-10-17C>T		intron	N/A	ENSP00000497767.1
	ALDOB	ENST00000648906.1		n.144C>T		non_coding_transcript_exon	Exon 1 of 2
	ALDOB	ENST00000648064.1		c.-10-17C>T		intron	N/A	ENSP00000497990.1

Frequencies

GnomAD3 genomes AF: 0.00172 AC: 262 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00256

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00184 AC: 460 AN: 249968 AF XY: 0.00185

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.000813

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00335

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00198 AC: 2784 AN: 1403776 Hom.: 4 Cov.: 24 AF XY: 0.00190 AC XY: 1332 AN XY: 701824

African (AFR) AF: 0.000372 AC: 12 AN: 32266

American (AMR) AF: 0.00114 AC: 51 AN: 44600

Ashkenazi Jewish (ASJ) AF: 0.000116 AC: 3 AN: 25790

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39400

South Asian (SAS) AF: 0.000647 AC: 55 AN: 84948

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53296

Middle Eastern (MID) AF: 0.00247 AC: 14 AN: 5666

European-Non Finnish (NFE) AF: 0.00224 AC: 2376 AN: 1059304

Other (OTH) AF: 0.00164 AC: 96 AN: 58506

GnomAD4 genome AF: 0.00173 AC: 263 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74424

African (AFR) AF: 0.000337 AC: 14 AN: 41528

American (AMR) AF: 0.00144 AC: 22 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00256 AC: 174 AN: 68012

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00136 Hom.: 0

Bravo AF: 0.00145

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.54
PhyloP100		-0.53
PromoterAI		-0.035	Neutral
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: rs182858853; hg19: chr9-104193196;