chr14-74072618-AAAAC-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005589.4(ALDH6A1):​c.112-11_112-8delGTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0148 in 1,606,608 control chromosomes in the GnomAD database, including 767 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (329 hom., cov: 31)
  • Exomes 𝑓: 0.012 (438 hom.)
• Consequence: ALDH6A1 NM_005589.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.925
• 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 -16 ACMG points.

• BP6: Variant 14-74072618-AAAAC-A is Benign according to our data. Variant chr14-74072618-AAAAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 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.112-11_112-8delGTTT		splice_region intron	N/A	NP_005580.1	A0A024R6G4
	ALDH6A1	NM_001278593.2		c.112-11_112-8delGTTT		splice_region intron	N/A	NP_001265522.1	Q02252-2
	ALDH6A1	NM_001278594.2		c.-514-11_-514-8delGTTT		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.112-11_112-8delGTTT		splice_region intron	N/A	ENSP00000450436.1	Q02252-1
	ALDH6A1	ENST00000554231.5	TSL:1	n.210-11_210-8delGTTT		splice_region intron	N/A
	ALDH6A1	ENST00000554501.5	TSL:1	n.167-11_167-8delGTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0413 AC: 6280 AN: 152010 Hom.: 323 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0374

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.00828

Gnomad OTH AF: 0.0368

GnomAD2 exomes AF: 0.0191 AC: 4679 AN: 244930 AF XY: 0.0181

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0308

Gnomad EAS exome AF: 0.00155

Gnomad FIN exome AF: 0.00251

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0120 AC: 17399 AN: 1454480 Hom.: 438 AF XY: 0.0121 AC XY: 8787 AN XY: 723850

African (AFR) AF: 0.130 AC: 4329 AN: 33322

American (AMR) AF: 0.0145 AC: 648 AN: 44646

Ashkenazi Jewish (ASJ) AF: 0.0299 AC: 779 AN: 26050

East Asian (EAS) AF: 0.00175 AC: 69 AN: 39506

South Asian (SAS) AF: 0.0277 AC: 2385 AN: 86032

European-Finnish (FIN) AF: 0.00230 AC: 120 AN: 52142

Middle Eastern (MID) AF: 0.0380 AC: 219 AN: 5758

European-Non Finnish (NFE) AF: 0.00692 AC: 7662 AN: 1106924

Other (OTH) AF: 0.0198 AC: 1188 AN: 60100

GnomAD4 genome AF: 0.0415 AC: 6315 AN: 152128 Hom.: 329 Cov.: 31 AF XY: 0.0402 AC XY: 2988 AN XY: 74398

African (AFR) AF: 0.122 AC: 5056 AN: 41426

American (AMR) AF: 0.0213 AC: 325 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0374 AC: 130 AN: 3472

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.0280 AC: 135 AN: 4830

European-Finnish (FIN) AF: 0.00113 AC: 12 AN: 10606

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00828 AC: 563 AN: 68020

Other (OTH) AF: 0.0378 AC: 80 AN: 2114

Alfa AF: 0.00784 Hom.: 4

Bravo AF: 0.0465

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism (auto)

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: rs370924173; hg19: chr14-74539321; COSMIC: COSV63246827; COSMIC: COSV63246827;