14-74057826-A-G

Variant names:

• chr14-74057826-A-G
• rs1536
• NM_005589.4:c.*2816T>C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_005589.4(ALDH6A1):​c.*2816T>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 0.139 in 1,032,704 control chromosomes in the GnomAD database, including 10,714 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1243 hom., cov: 32)
  • Exomes 𝑓: 0.14 (9471 hom.)
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 14-74057826-A-G is Benign according to our data. Variant chr14-74057826-A-G is described in ClinVar as [Benign]. Clinvar id is 887992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.183 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH6A1	NM_005589.4	c.*2816T>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000553458.6	NP_005580.1
BBOF1	NM_025057.3	c.1578+568A>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	c.*2816T>C		3_prime_UTR_variant	Exon 12 of 12	1	NM_005589.4	ENSP00000450436.1
BBOF1	ENST00000394009.5	c.1578+568A>G		intron_variant	Intron 11 of 11	2	NM_025057.3	ENSP00000377577.3
BBOF1	ENST00000492026.4	n.1379+568A>G		intron_variant	Intron 9 of 12	2

Frequencies

GnomAD3 genomes AF: 0.112 AC: 16971 AN: 152126 Hom.: 1242 Cov.: 32

Gnomad AFR AF: 0.0283

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.0760

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.147

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.110

GnomAD4 exome AF: 0.143 AC: 126344 AN: 880460 Hom.: 9471 Cov.: 31 AF XY: 0.143 AC XY: 58739 AN XY: 411032

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.255

Gnomad4 ASJ exome AF: 0.128

Gnomad4 EAS exome AF: 0.0666

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.135

GnomAD4 genome AF: 0.111 AC: 16972 AN: 152244 Hom.: 1243 Cov.: 32 AF XY: 0.111 AC XY: 8277 AN XY: 74428

Gnomad4 AFR AF: 0.0283

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.0762

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.147

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.108

Alfa AF: 0.141 Hom.: 668

Bravo AF: 0.117

Asia WGS AF: 0.0710 AC: 248 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	-0.38
CADD	Benign	13
DANN	Benign	0.70

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: rs1536; hg19: chr14-74524529;