chr5-126595191-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_001182.5(ALDH7A1):c.8G>C(p.Arg3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,399,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.987

Publications

1 publications found

Variant links:

Genes affected

ALDH7A1 (HGNC:877): (aldehyde dehydrogenase 7 family member A1) The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [provided by RefSeq, Jan 2011]

ALDH7A1 Gene-Disease associations (from GenCC):

pyridoxine-dependent epilepsy
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen
pyridoxine-dependent epilepsy caused by ALDH7A1 mutant
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALDH7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.36846 (below the threshold of 3.09). Trascript score misZ: 0.93117 (below the threshold of 3.09). GenCC associations: The gene is linked to pyridoxine-dependent epilepsy, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5 link	c.8G>C	p.Arg3Pro	missense_variant	Exon 1 of 18	ENST00000409134.8	NP_001173.2	P49419-1
ALDH7A1	NM_001202404.2 link	c.8G>C	p.Arg3Pro	missense_variant	Exon 1 of 16		NP_001189333.2	P49419-4
ALDH7A1	NM_001201377.2 link	c.-77G>C		5_prime_UTR_variant	Exon 1 of 18		NP_001188306.1	P49419-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 link	c.8G>C	p.Arg3Pro	missense_variant	Exon 1 of 18	1	NM_001182.5	ENSP00000387123.3		P49419-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000642

AC:

AN:

155706

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1399738

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

690432

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31606

American (AMR)

AF:

0.00

AC:

AN:

35742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25190

East Asian (EAS)

AF:

0.00

AC:

AN:

35746

South Asian (SAS)

AF:

0.0000378

AC:

AN:

79306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49328

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1079100

Other (OTH)

AF:

0.00

AC:

AN:

58022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 06, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R3P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3P variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0019

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.027

T;T;T;.;T;.;.;.;T;T;T;T

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.023

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.90

D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.069

MetaRNN

Benign

0.41

T;T;T;T;T;T;T;T;T;T;D;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

1.3

.;L;.;.;.;.;.;L;.;.;.;.

PhyloP100

0.99

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.66

.;N;.;.;.;.;.;N;.;.;N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.0040

.;D;.;.;.;.;.;D;.;.;D;D

Sift4G

Benign

0.10

.;T;.;.;.;.;.;T;.;D;.;.

Polyphen

0.0

.;B;.;.;.;.;.;.;.;.;.;.

Vest4

0.32, 0.41, 0.51

MutPred

0.56

Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);Loss of MoRF binding (P = 0);.;Loss of MoRF binding (P = 0);

MVP

0.93

MPC

0.33

ClinPred

0.54

GERP RS

3.5

PromoterAI

-0.44

Neutral

(source)

Varity_R

0.19

gMVP

0.74

Mutation Taster

=81/19

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over