14-74057962-T-C

Variant names:

• chr14-74057962-T-C
• rs10139971
• NM_005589.4:c.*2680A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005589.4(ALDH6A1):​c.*2680A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00697 in 905,568 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (56 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (41 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0330

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=-0.52).
• BP6: Variant 14-74057962-T-C is Benign according to our data. Variant chr14-74057962-T-C is described in ClinVar as [Benign]. Clinvar id is 887994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH6A1	NM_005589.4	c.*2680A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000553458.6	NP_005580.1
BBOF1	NM_025057.3	c.1578+704T>C		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	c.*2680A>G		3_prime_UTR_variant	Exon 12 of 12	1	NM_005589.4	ENSP00000450436.1
BBOF1	ENST00000394009.5	c.1578+704T>C		intron_variant	Intron 11 of 11	2	NM_025057.3	ENSP00000377577.3
BBOF1	ENST00000492026.4	n.1379+704T>C		intron_variant	Intron 9 of 12	2

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2813 AN: 152164 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00463

Gnomad OTH AF: 0.0163

GnomAD4 exome AF: 0.00462 AC: 3478 AN: 753286 Hom.: 41 Cov.: 10 AF XY: 0.00457 AC XY: 1601 AN XY: 350670

Gnomad4 AFR exome AF: 0.0542

Gnomad4 AMR exome AF: 0.0105

Gnomad4 ASJ exome AF: 0.0185

Gnomad4 EAS exome AF: 0.00115

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.00874

GnomAD4 genome AF: 0.0186 AC: 2831 AN: 152282 Hom.: 56 Cov.: 32 AF XY: 0.0181 AC XY: 1346 AN XY: 74454

Gnomad4 AFR AF: 0.0505

Gnomad4 AMR AF: 0.0109

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0240

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00463

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0116 Hom.: 4

Bravo AF: 0.0200

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Methylmalonate semialdehyde dehydrogenase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.4
DANN	Benign	0.75

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: rs10139971; hg19: chr14-74524665;