chr14-74059108-C-T

Variant names:

• chr14-74059108-C-T
• rs1047039253
• NM_005589.4:c.*1534G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005589.4(ALDH6A1):​c.*1534G>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 0.0000736 in 149,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.363
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

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.*1534G>A		3_prime_UTR	Exon 12 of 12	NP_005580.1	A0A024R6G4
	BBOF1	NM_025057.3	MANE Select	c.1578+1850C>T		intron	N/A	NP_079333.2	Q8ND07
	ALDH6A1	NM_001278593.2		c.*1534G>A		3_prime_UTR	Exon 12 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.*1534G>A		3_prime_UTR	Exon 12 of 12	ENSP00000450436.1	Q02252-1
	BBOF1	ENST00000394009.5	TSL:2 MANE Select	c.1578+1850C>T		intron	N/A	ENSP00000377577.3	Q8ND07
	ALDH6A1	ENST00000901407.1		c.*1534G>A		3_prime_UTR	Exon 11 of 11	ENSP00000571466.1

Frequencies

GnomAD3 genomes AF: 0.0000669 AC: 9 AN: 134626 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00122

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00370

Gnomad NFE AF: 0.0000633

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 2 AN: 14806 Hom.: 0 Cov.: 0 AF XY: 0.000227 AC XY: 2 AN XY: 8810

African (AFR) AF: 0.00 AC: 0 AN: 96

American (AMR) AF: 0.00 AC: 0 AN: 306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 256

East Asian (EAS) AF: 0.00 AC: 0 AN: 250

South Asian (SAS) AF: 0.00 AC: 0 AN: 2890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 40

European-Non Finnish (NFE) AF: 0.000212 AC: 2 AN: 9416

Other (OTH) AF: 0.00 AC: 0 AN: 642

GnomAD4 genome AF: 0.0000669 AC: 9 AN: 134624 Hom.: 0 Cov.: 31 AF XY: 0.0000616 AC XY: 4 AN XY: 64980

African (AFR) AF: 0.00 AC: 0 AN: 35688

American (AMR) AF: 0.00 AC: 0 AN: 13304

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 4 AN: 3276

East Asian (EAS) AF: 0.00 AC: 0 AN: 4790

South Asian (SAS) AF: 0.00 AC: 0 AN: 4322

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7074

Middle Eastern (MID) AF: 0.00407 AC: 1 AN: 246

European-Non Finnish (NFE) AF: 0.0000633 AC: 4 AN: 63222

Other (OTH) AF: 0.00 AC: 0 AN: 1816

Alfa AF: 0.000142 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Methylmalonate semialdehyde dehydrogenase deficiency (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.5
DANN	Benign	0.67
PhyloP100		-0.36

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: rs1047039253; hg19: chr14-74525811;