Genetic Variant ALDH6A1:c.112-11_112-8dupGTTT (chr14-74072618-A-AAAAC) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_005589.4(ALDH6A1):c.112-11_112-8dupGTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,607,754 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0096 ( 23 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 16 hom. )

Consequence

ALDH6A1
NM_005589.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.00

Variant links:

Genes affected

ALDH6A1 (HGNC:7179): (aldehyde dehydrogenase 6 family member A1) This gene encodes a member of the aldehyde dehydrogenase protein family. The encoded protein is a mitochondrial methylmalonate semialdehyde dehydrogenase that plays a role in the valine and pyrimidine catabolic pathways. This protein catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA. Methylmalonate semialdehyde dehydrogenase deficiency is characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]

ALDH6A1 links:

BBOF1 (HGNC:19855): (basal body orientation factor 1) Predicted to be involved in motile cilium assembly. Predicted to be located in ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

BBOF1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 14-74072618-A-AAAAC is Benign according to our data. Variant chr14-74072618-A-AAAAC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 314184.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00962 (1463/152150) while in subpopulation AFR AF= 0.0328 (1361/41442). AF 95% confidence interval is 0.0314. There are 23 homozygotes in gnomad4. There are 666 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH6A1	NM_005589.4 link	c.112-11_112-8dupGTTT		splice_region_variant, intron_variant	Intron 2 of 11	ENST00000553458.6	NP_005580.1	Q02252-1A0A024R6G4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH6A1	ENST00000553458.6 link	c.112-8_112-7insGTTT		splice_region_variant, intron_variant	Intron 2 of 11	1	NM_005589.4	ENSP00000450436.1		Q02252-1

Frequencies

GnomAD3 genomes

AF:

0.00962

AC:

1463

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00334

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00274

AC:

670

AN:

244930

Hom.:

AF XY:

0.00205

AC XY:

272

AN XY:

132790

show subpopulations

Gnomad AFR exome

AF:

0.0345

Gnomad AMR exome

AF:

0.00172

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.000594

Gnomad FIN exome

AF:

0.0000492

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00126

AC:

1833

AN:

1455604

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

805

AN XY:

724386

show subpopulations

Gnomad4 AFR exome

AF:

0.0322

Gnomad4 AMR exome

AF:

0.00199

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.0000758

Gnomad4 SAS exome

AF:

0.000767

Gnomad4 FIN exome

AF:

0.0000766

Gnomad4 NFE exome

AF:

0.000373

Gnomad4 OTH exome

AF:

0.00269

GnomAD4 genome

AF:

0.00962

AC:

1463

AN:

152150

Hom.:

Cov.:

AF XY:

0.00895

AC XY:

666

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0328

Gnomad4 AMR

AF:

0.00334

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00520

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Methylmalonate semialdehyde dehydrogenase deficiency

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over