14-74058151-C-A

Variant names:

• chr14-74058151-C-A
• rs181822532
• NM_005589.4:c.*2491G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_005589.4(ALDH6A1):​c.*2491G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00044 in 152,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH6A1 NM_005589.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.462
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 14-74058151-C-A is Benign according to our data. Variant chr14-74058151-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 887996.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00044 (67/152114) while in subpopulation EAS AF = 0.0118 (61/5172). AF 95% confidence interval is 0.00942. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005589.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH6A1	NM_005589.4	MANE Select	c.*2491G>T		3_prime_UTR	Exon 12 of 12	NP_005580.1	A0A024R6G4
	BBOF1	NM_025057.3	MANE Select	c.1578+893C>A		intron	N/A	NP_079333.2	Q8ND07
	ALDH6A1	NM_001278593.2		c.*2491G>T		3_prime_UTR	Exon 12 of 12	NP_001265522.1	Q02252-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH6A1	ENST00000553458.6	TSL:1 MANE Select	c.*2491G>T		3_prime_UTR	Exon 12 of 12	ENSP00000450436.1	Q02252-1
	BBOF1	ENST00000394009.5	TSL:2 MANE Select	c.1578+893C>A		intron	N/A	ENSP00000377577.3	Q8ND07
	BBOF1	ENST00000901146.1		c.1434+893C>A		intron	N/A	ENSP00000571205.1

Frequencies

GnomAD3 genomes AF: 0.000441 AC: 67 AN: 151998 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1174 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 600

African (AFR) AF: 0.00 AC: 0 AN: 20

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.00 AC: 0 AN: 14

South Asian (SAS) AF: 0.00 AC: 0 AN: 28

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1050

Other (OTH) AF: 0.00 AC: 0 AN: 48

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152114 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 41 AN XY: 74370

African (AFR) AF: 0.00 AC: 0 AN: 41502

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5172

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000438

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonate semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.91
PhyloP100		0.46

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

Other links and lift over

dbSNP: rs181822532; hg19: chr14-74524854;