rs2306618

Variant names:

• chr5-126552104-T-C
• rs2306618
• NM_001182.5:c.1234A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-126552104-T-C
• chr5-126552104-T-A
• chr5-126552104-T-G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001182.5(ALDH7A1):​c.1234A>G​(p.Thr412Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,614,082 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T412I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0033 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (97 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 5.05
• Publications: 12 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: Orphanet, Illumina, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_001182.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-126552103-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 835957.
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056553185).
• BP6: Variant 5-126552104-T-C is Benign according to our data. Variant chr5-126552104-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. 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
	ALDH7A1	NM_001182.5	MANE Select	c.1234A>G	p.Thr412Ala	missense	Exon 14 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.1150A>G	p.Thr384Ala	missense	Exon 14 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.1042A>G	p.Thr348Ala	missense	Exon 12 of 16	NP_001189333.2	P49419-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.1234A>G	p.Thr412Ala	missense	Exon 14 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.1279A>G	p.Thr427Ala	missense	Exon 15 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.1276A>G	p.Thr426Ala	missense	Exon 15 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152168 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.0771

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00683 AC: 1715 AN: 251254 AF XY: 0.00641

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0115

Gnomad EAS exome AF: 0.0813

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00235 AC: 3433 AN: 1461796 Hom.: 97 Cov.: 32 AF XY: 0.00232 AC XY: 1689 AN XY: 727198

African (AFR) AF: 0.000209 AC: 7 AN: 33476

American (AMR) AF: 0.000201 AC: 9 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 308 AN: 26130

East Asian (EAS) AF: 0.0645 AC: 2559 AN: 39674

South Asian (SAS) AF: 0.00134 AC: 116 AN: 86254

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000138 AC: 154 AN: 1111964

Other (OTH) AF: 0.00447 AC: 270 AN: 60392

GnomAD4 genome AF: 0.00333 AC: 507 AN: 152286 Hom.: 15 Cov.: 32 AF XY: 0.00373 AC XY: 278 AN XY: 74484

African (AFR) AF: 0.000602 AC: 25 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.0773 AC: 401 AN: 5186

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000927 Hom.: 2

Bravo AF: 0.00371

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00668 AC: 811

Asia WGS AF: 0.0320 AC: 110 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Pyridoxine-dependent epilepsy (4)
-	-	3	not specified (3)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.0024
Eigen_PC	Benign	0.058
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.1
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.59
Sift	Benign	0.59	T
Sift4G	Benign	0.90	T
Polyphen		0.28	B
Vest4		0.48
MVP		0.87
MPC		0.27
ClinPred		0.10	T
GERP RS		4.9
Varity_R		0.71
gMVP		0.86
Mutation Taster		=37/63	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: rs2306618; hg19: chr5-125887796; COSMIC: COSV63160896; COSMIC: COSV63160896;