rs1555376629

Variant names:

• chr14-74065278-TG-T
• rs1555376629
• NM_005589.4:c.1306delC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005589.4(ALDH6A1):​c.1306delC​(p.Gln436ArgfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH6A1 NM_005589.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.523
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-74065278-TG-T is Pathogenic according to our data. Variant chr14-74065278-TG-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 445855.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005589.4. 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
	ALDH6A1	NM_005589.4	MANE Select	c.1306delC	p.Gln436ArgfsTer3	frameshift	Exon 10 of 12	NP_005580.1	A0A024R6G4
	BBOF1	NM_025057.3	MANE Select	c.*581delG		3_prime_UTR	Exon 12 of 12	NP_079333.2	Q8ND07
	ALDH6A1	NM_001278593.2		c.1267delC	p.Gln423ArgfsTer3	frameshift	Exon 10 of 12	NP_001265522.1	Q02252-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH6A1	ENST00000553458.6	TSL:1 MANE Select	c.1306delC	p.Gln436ArgfsTer3	frameshift	Exon 10 of 12	ENSP00000450436.1	Q02252-1
	BBOF1	ENST00000394009.5	TSL:2 MANE Select	c.*581delG		3_prime_UTR	Exon 12 of 12	ENSP00000377577.3	Q8ND07
	ALDH6A1	ENST00000554501.5	TSL:1	n.1524delC		non_coding_transcript_exon	Exon 10 of 12

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs1555376629; hg19: chr14-74531981;