NM_005589.4:c.785C>A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_005589.4(ALDH6A1):c.785C>A(p.Ser262Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALDH6A1
NM_005589.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.99

Publications

2 publications found

Variant links:

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]

ALDH6A1 links:

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]

BBOF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.978

PP5

Variant 14-74068927-G-T is Pathogenic according to our data. Variant chr14-74068927-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 208070.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH6A1	NM_005589.4	MANE Select	c.785C>A	p.Ser262Tyr	missense	Exon 7 of 12	NP_005580.1
ALDH6A1	NM_001278593.2		c.746C>A	p.Ser249Tyr	missense	Exon 7 of 12	NP_001265522.1
ALDH6A1	NM_001278594.2		c.323C>A	p.Ser108Tyr	missense	Exon 7 of 12	NP_001265523.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH6A1	ENST00000553458.6	TSL:1 MANE Select	c.785C>A	p.Ser262Tyr	missense	Exon 7 of 12	ENSP00000450436.1
ALDH6A1	ENST00000554501.5	TSL:1	n.1003C>A		non_coding_transcript_exon	Exon 7 of 12
ALDH6A1	ENST00000350259.8	TSL:2	c.746C>A	p.Ser249Tyr	missense	Exon 7 of 12	ENSP00000342564.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Methylmalonate semialdehyde dehydrogenase deficiency

Pathogenic:1

May 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.7

PhyloP100

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

0.60

Vest4

0.99

MutPred

0.89

Loss of glycosylation at S262 (P = 0.0606)

MVP

0.99

MPC

0.79

ClinPred

1.0

GERP RS

6.0

PromoterAI

-0.0020

Neutral

(source)

Varity_R

0.99

gMVP

0.96

Mutation Taster

=171/129

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over