14-74058125-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005589.4(ALDH6A1):c.*2517T>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 0.01 in 156,616 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (32 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0130

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-74058125-A-G is Benign according to our data. Variant chr14-74058125-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 887995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1566/152214) while in subpopulation AFR AF= 0.0361 (1499/41528). AF 95% confidence interval is 0.0346. There are 32 homozygotes in gnomad4. There are 741 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 32 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH6A1	NM_005589.4	c.*2517T>C		3_prime_UTR_variant	12/12	ENST00000553458.6
BBOF1	NM_025057.3	c.1578+867A>G		intron_variant		ENST00000394009.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH6A1	ENST00000553458.6	c.*2517T>C		3_prime_UTR_variant	12/12	1	NM_005589.4	P1
BBOF1	ENST00000394009.5	c.1578+867A>G		intron_variant		2	NM_025057.3	P1
BBOF1	ENST00000492026.4	n.1379+867A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1563 AN: 152096 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0361

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.000909 AC: 4 AN: 4402 Hom.: 0 Cov.: 4 AF XY: 0.000885 AC XY: 2 AN XY: 2260

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0154

GnomAD4 genome AF: 0.0103 AC: 1566 AN: 152214 Hom.: 32 Cov.: 32 AF XY: 0.00995 AC XY: 741 AN XY: 74440

Gnomad4 AFR AF: 0.0361

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00888 Hom.: 3

Bravo AF: 0.0119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonate semialdehyde dehydrogenase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
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	-0.87
Cadd	Benign	6.7
Dann	Benign	0.86

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: rs145794069; hg19: chr14-74524828;