14-74058708-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005589.4(ALDH6A1):c.*1934T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.241 in 151,910 control chromosomes in the GnomAD database, including 5,000 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4999 hom., cov: 30)
  • Exomes 𝑓: 0.22 (1 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.14

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-74058708-A-G is Benign according to our data. Variant chr14-74058708-A-G is described in ClinVar as [Benign]. Clinvar id is 884866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH6A1	NM_005589.4	c.*1934T>C		3_prime_UTR_variant	12/12	ENST00000553458.6
BBOF1	NM_025057.3	c.1578+1450A>G		intron_variant		ENST00000394009.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH6A1	ENST00000553458.6	c.*1934T>C		3_prime_UTR_variant	12/12	1	NM_005589.4	P1
BBOF1	ENST00000394009.5	c.1578+1450A>G		intron_variant		2	NM_025057.3	P1
BBOF1	ENST00000492026.4	n.1379+1450A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.241 AC: 36571 AN: 151740 Hom.: 4983 Cov.: 30

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.299

Gnomad AMR AF: 0.191

Gnomad ASJ AF: 0.190

Gnomad EAS AF: 0.245

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.234

GnomAD4 exome AF: 0.222 AC: 12 AN: 54 Hom.: 1 Cov.: 0 AF XY: 0.222 AC XY: 8 AN XY: 36

Gnomad4 AMR exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.196

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.241 AC: 36617 AN: 151856 Hom.: 4999 Cov.: 30 AF XY: 0.242 AC XY: 17980 AN XY: 74218

Gnomad4 AFR AF: 0.351

Gnomad4 AMR AF: 0.191

Gnomad4 ASJ AF: 0.190

Gnomad4 EAS AF: 0.244

Gnomad4 SAS AF: 0.459

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.187

Gnomad4 OTH AF: 0.236

Alfa AF: 0.210 Hom.: 1314

Bravo AF: 0.243

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Methylmalonate semialdehyde dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.59
Dann	Benign	0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs10200; hg19: chr14-74525411;