NM_005589.4:c.*2816T>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId 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.

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.*2816T>C		3_prime_UTR	Exon 12 of 12	NP_005580.1	A0A024R6G4
	BBOF1	NM_025057.3	MANE Select	c.1578+568A>G		intron	N/A	NP_079333.2	Q8ND07
	ALDH6A1	NM_001278593.2		c.*2816T>C		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.*2816T>C		3_prime_UTR	Exon 12 of 12	ENSP00000450436.1	Q02252-1
	BBOF1	ENST00000394009.5	TSL:2 MANE Select	c.1578+568A>G		intron	N/A	ENSP00000377577.3	Q8ND07
	BBOF1	ENST00000901146.1		c.1434+568A>G		intron	N/A	ENSP00000571205.1

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

African (AFR) AF: 0.0178 AC: 293 AN: 16434

American (AMR) AF: 0.255 AC: 833 AN: 3266

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 792 AN: 6182

East Asian (EAS) AF: 0.0666 AC: 373 AN: 5604

South Asian (SAS) AF: 0.107 AC: 2620 AN: 24558

European-Finnish (FIN) AF: 0.157 AC: 504 AN: 3214

Middle Eastern (MID) AF: 0.0903 AC: 162 AN: 1794

European-Non Finnish (NFE) AF: 0.148 AC: 116773 AN: 789782

Other (OTH) AF: 0.135 AC: 3994 AN: 29626

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

African (AFR) AF: 0.0283 AC: 1174 AN: 41556

American (AMR) AF: 0.189 AC: 2890 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3470

East Asian (EAS) AF: 0.0762 AC: 395 AN: 5184

South Asian (SAS) AF: 0.106 AC: 510 AN: 4828

European-Finnish (FIN) AF: 0.147 AC: 1563 AN: 10602

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9663 AN: 68006

Other (OTH) AF: 0.108 AC: 229 AN: 2112

Alfa AF: 0.139 Hom.: 785

Bravo AF: 0.117

Asia WGS AF: 0.0710 AC: 248 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	-0.38
CADD	Benign	13
DANN	Benign	0.70
PhyloP100		1.1
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: rs1536; hg19: chr14-74524529; COSMIC: COSV107450224; COSMIC: COSV107450224;