14-74072618-AAAACAAACAAAC-AAAACAAACAAACAAAC

Variant names:

• chr14-74072618-A-AAAAC
• rs370924173
• NM_005589.4:c.112-11_112-8dupGTTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005589.4(ALDH6A1):​c.112-11_112-8dupGTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,607,754 control chromosomes in the GnomAD database, including 39 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0096 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (16 hom.)
• Consequence: ALDH6A1 NM_005589.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.00
• 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 -9 ACMG points.

• BP6: Variant 14-74072618-A-AAAAC is Benign according to our data. Variant chr14-74072618-A-AAAAC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 314184.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00962 (1463/152150) while in subpopulation AFR AF = 0.0328 (1361/41442). AF 95% confidence interval is 0.0314. There are 23 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

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.112-11_112-8dupGTTT		splice_region intron	N/A	NP_005580.1	A0A024R6G4
	ALDH6A1	NM_001278593.2		c.112-11_112-8dupGTTT		splice_region intron	N/A	NP_001265522.1	Q02252-2
	ALDH6A1	NM_001278594.2		c.-514-11_-514-8dupGTTT		splice_region intron	N/A	NP_001265523.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH6A1	ENST00000553458.6	TSL:1 MANE Select	c.112-8_112-7insGTTT		splice_region intron	N/A	ENSP00000450436.1	Q02252-1
	ALDH6A1	ENST00000554231.5	TSL:1	n.210-8_210-7insGTTT		splice_region intron	N/A
	ALDH6A1	ENST00000554501.5	TSL:1	n.167-8_167-7insGTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1463 AN: 152032 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00274 AC: 670 AN: 244930 AF XY: 0.00205

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.0000492

Gnomad NFE exome AF: 0.000345

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00126 AC: 1833 AN: 1455604 Hom.: 16 Cov.: 33 AF XY: 0.00111 AC XY: 805 AN XY: 724386

African (AFR) AF: 0.0322 AC: 1072 AN: 33338

American (AMR) AF: 0.00199 AC: 89 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26074

East Asian (EAS) AF: 0.0000758 AC: 3 AN: 39552

South Asian (SAS) AF: 0.000767 AC: 66 AN: 86078

European-Finnish (FIN) AF: 0.0000766 AC: 4 AN: 52202

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5758

European-Non Finnish (NFE) AF: 0.000373 AC: 413 AN: 1107798

Other (OTH) AF: 0.00269 AC: 162 AN: 60142

GnomAD4 genome AF: 0.00962 AC: 1463 AN: 152150 Hom.: 23 Cov.: 32 AF XY: 0.00895 AC XY: 666 AN XY: 74404

African (AFR) AF: 0.0328 AC: 1361 AN: 41442

American (AMR) AF: 0.00334 AC: 51 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000565 Hom.: 4

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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
PhyloP100		0.0
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs370924173; hg19: chr14-74539321;