NM_005589.4:c.*2680A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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 -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 VariationId 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.

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.*2680A>G		3_prime_UTR	Exon 12 of 12	NP_005580.1	A0A024R6G4
	BBOF1	NM_025057.3	MANE Select	c.1578+704T>C		intron	N/A	NP_079333.2	Q8ND07
	ALDH6A1	NM_001278593.2		c.*2680A>G		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.*2680A>G		3_prime_UTR	Exon 12 of 12	ENSP00000450436.1	Q02252-1
	BBOF1	ENST00000394009.5	TSL:2 MANE Select	c.1578+704T>C		intron	N/A	ENSP00000377577.3	Q8ND07
	BBOF1	ENST00000901146.1		c.1434+704T>C		intron	N/A	ENSP00000571205.1

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

African (AFR) AF: 0.0542 AC: 758 AN: 13992

American (AMR) AF: 0.0105 AC: 15 AN: 1432

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 89 AN: 4800

East Asian (EAS) AF: 0.00115 AC: 4 AN: 3470

South Asian (SAS) AF: 0.0214 AC: 339 AN: 15810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 932

Middle Eastern (MID) AF: 0.0308 AC: 46 AN: 1494

European-Non Finnish (NFE) AF: 0.00293 AC: 2010 AN: 686520

Other (OTH) AF: 0.00874 AC: 217 AN: 24836

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

African (AFR) AF: 0.0505 AC: 2098 AN: 41548

American (AMR) AF: 0.0109 AC: 167 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5194

South Asian (SAS) AF: 0.0240 AC: 116 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00463 AC: 315 AN: 68024

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0133 Hom.: 4

Bravo AF: 0.0200

Asia WGS AF: 0.0190 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Methylmalonate semialdehyde dehydrogenase deficiency (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.4
DANN	Benign	0.75
PhyloP100		0.033
Mutation Taster		=100/0	polymorphism

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: rs10139971; hg19: chr14-74524665;