rs147940248

Variant names:

• chr5-126550205-C-A
• rs147940248
• NM_001182.5:c.1406G>T

Your query was ambiguous. Multiple possible variants found:

• chr5-126550205-C-A
• chr5-126550205-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001182.5(ALDH7A1):​c.1406G>T​(p.Arg469Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,116 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R469H) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.06
• Publications: 6 publications found

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

ACMG classification

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	c.1406G>T	p.Arg469Leu	missense_variant	Exon 15 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.1322G>T	p.Arg441Leu	missense_variant	Exon 15 of 18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.1214G>T	p.Arg405Leu	missense_variant	Exon 13 of 16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.1406G>T	p.Arg469Leu	missense_variant	Exon 15 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.0000241 AC: 1 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;D;T;.;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.72	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.;.;.
PhyloP100		4.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	.;D;.;.;.;.;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.21	.;T;.;.;.;.;.;T
Sift4G	Benign	0.34	.;T;.;.;.;.;.;T
Polyphen		0.80	.;P;.;.;.;.;.;.
Vest4		0.72, 0.73
MutPred		0.68		Loss of MoRF binding (P = 0.0148);Loss of MoRF binding (P = 0.0148);.;.;.;.;.;.;
MVP		0.88
MPC		0.32
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.81
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -9

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

Other links and lift over

dbSNP: rs147940248; hg19: chr5-125885897;