14-74062957-T-G

Variant names:

• chr14-74062957-T-G
• rs9652369
• NM_005589.4:c.1503+1865A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005589.4(ALDH6A1):​c.1503+1865A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.561 in 152,040 control chromosomes in the GnomAD database, including 25,244 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25244 hom., cov: 31)
• Consequence: ALDH6A1 NM_005589.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.301
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH6A1	NM_005589.4	c.1503+1865A>C		intron_variant	Intron 11 of 11	ENST00000553458.6	NP_005580.1
BBOF1	NM_025057.3	c.1579-1731T>G		intron_variant	Intron 11 of 11	ENST00000394009.5	NP_079333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH6A1	ENST00000553458.6	c.1503+1865A>C		intron_variant	Intron 11 of 11	1	NM_005589.4	ENSP00000450436.1
BBOF1	ENST00000394009.5	c.1579-1731T>G		intron_variant	Intron 11 of 11	2	NM_025057.3	ENSP00000377577.3

Frequencies

GnomAD3 genomes AF: 0.561 AC: 85250 AN: 151922 Hom.: 25210 Cov.: 31

Gnomad AFR AF: 0.701

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.481

Gnomad EAS AF: 0.893

Gnomad SAS AF: 0.706

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.548

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.561 AC: 85331 AN: 152040 Hom.: 25244 Cov.: 31 AF XY: 0.561 AC XY: 41673 AN XY: 74304

African (AFR) AF: 0.701 AC: 29053 AN: 41468

American (AMR) AF: 0.522 AC: 7980 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.481 AC: 1667 AN: 3468

East Asian (EAS) AF: 0.893 AC: 4619 AN: 5172

South Asian (SAS) AF: 0.707 AC: 3397 AN: 4808

European-Finnish (FIN) AF: 0.432 AC: 4561 AN: 10564

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.473 AC: 32169 AN: 67972

Other (OTH) AF: 0.546 AC: 1152 AN: 2110

Alfa AF: 0.419 Hom.: 1701

Bravo AF: 0.583

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.1
DANN	Benign	0.86
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism (auto)

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: rs9652369; hg19: chr14-74529660;