14-74057648-T-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.*2994A>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 0.0102 in 1,330,040 control chromosomes in the GnomAD database, including 384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (201 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (183 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.350

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=-0.84).
• BP6: Variant 14-74057648-T-G is Benign according to our data. Variant chr14-74057648-T-G is described in ClinVar as [Benign]. Clinvar id is 887990.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0941 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH6A1	NM_005589.4	c.*2994A>C		3_prime_UTR_variant	12/12	ENST00000553458.6
BBOF1	NM_025057.3	c.1578+390T>G		intron_variant		ENST00000394009.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH6A1	ENST00000553458.6	c.*2994A>C		3_prime_UTR_variant	12/12	1	NM_005589.4	P1
BBOF1	ENST00000394009.5	c.1578+390T>G		intron_variant		2	NM_025057.3	P1
BBOF1	ENST00000492026.4	n.1379+390T>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0321 AC: 4877 AN: 152162 Hom.: 196 Cov.: 32

Gnomad AFR AF: 0.0961

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00507

Gnomad OTH AF: 0.0287

GnomAD3 exomes AF: 0.0135 AC: 2769 AN: 205596 Hom.: 75 AF XY: 0.0129 AC XY: 1473 AN XY: 114244

Gnomad AFR exome AF: 0.0952

Gnomad AMR exome AF: 0.00907

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.000314

Gnomad SAS exome AF: 0.0242

Gnomad FIN exome AF: 0.000359

Gnomad NFE exome AF: 0.00473

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00731 AC: 8605 AN: 1177760 Hom.: 183 Cov.: 32 AF XY: 0.00773 AC XY: 4504 AN XY: 582720

Gnomad4 AFR exome AF: 0.0963

Gnomad4 AMR exome AF: 0.00926

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.000361

Gnomad4 SAS exome AF: 0.0228

Gnomad4 FIN exome AF: 0.000179

Gnomad4 NFE exome AF: 0.00339

Gnomad4 OTH exome AF: 0.0122

GnomAD4 genome AF: 0.0322 AC: 4910 AN: 152280 Hom.: 201 Cov.: 32 AF XY: 0.0312 AC XY: 2322 AN XY: 74474

Gnomad4 AFR AF: 0.0966

Gnomad4 AMR AF: 0.0181

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0242

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00507

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0174 Hom.: 14

Bravo AF: 0.0354

Asia WGS AF: 0.0250 AC: 88 AN: 3474

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	-0.84
Cadd	Benign	4.1
Dann	Benign	0.63

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: rs114251476; hg19: chr14-74524351;