rs12514417

Variant names:

• chr5-126552023-T-G
• rs12514417
• NM_001182.5:c.1315A>C

Your query was ambiguous. Multiple possible variants found:

• chr5-126552023-T-G
• chr5-126552023-T-C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001182.5(ALDH7A1):​c.1315A>C​(p.Lys439Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0959 in 1,609,982 control chromosomes in the GnomAD database, including 8,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K439N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.088 (711 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7546 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002109
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 4.92
• Publications: 33 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 -17 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, 4 uncertain in NM_001182.5
• 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=0.00204584).
• BP6: Variant 5-126552023-T-G is Benign according to our data. Variant chr5-126552023-T-G is described in ClinVar as Benign. ClinVar VariationId is 128346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 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.1315A>C	p.Lys439Gln	missense splice_region	Exon 14 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.1231A>C	p.Lys411Gln	missense splice_region	Exon 14 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.1123A>C	p.Lys375Gln	missense splice_region	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.1315A>C	p.Lys439Gln	missense splice_region	Exon 14 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.1360A>C	p.Lys454Gln	missense splice_region	Exon 15 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.1357A>C	p.Lys453Gln	missense splice_region	Exon 15 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13300 AN: 152114 Hom.: 705 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0783

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.0765

GnomAD2 exomes AF: 0.114 AC: 28669 AN: 251026 AF XY: 0.109

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0768

Gnomad EAS exome AF: 0.142

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0968 AC: 141066 AN: 1457750 Hom.: 7546 Cov.: 31 AF XY: 0.0956 AC XY: 69359 AN XY: 725456

African (AFR) AF: 0.0402 AC: 1342 AN: 33412

American (AMR) AF: 0.226 AC: 10082 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 1963 AN: 26110

East Asian (EAS) AF: 0.123 AC: 4898 AN: 39676

South Asian (SAS) AF: 0.0793 AC: 6828 AN: 86148

European-Finnish (FIN) AF: 0.130 AC: 6956 AN: 53384

Middle Eastern (MID) AF: 0.0544 AC: 273 AN: 5016

European-Non Finnish (NFE) AF: 0.0930 AC: 103169 AN: 1109104

Other (OTH) AF: 0.0923 AC: 5555 AN: 60208

GnomAD4 genome AF: 0.0875 AC: 13322 AN: 152232 Hom.: 711 Cov.: 32 AF XY: 0.0893 AC XY: 6645 AN XY: 74430

African (AFR) AF: 0.0436 AC: 1810 AN: 41542

American (AMR) AF: 0.141 AC: 2160 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0812 AC: 282 AN: 3472

East Asian (EAS) AF: 0.151 AC: 781 AN: 5178

South Asian (SAS) AF: 0.0779 AC: 376 AN: 4824

European-Finnish (FIN) AF: 0.128 AC: 1355 AN: 10600

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0925 AC: 6290 AN: 68010

Other (OTH) AF: 0.0799 AC: 169 AN: 2114

Alfa AF: 0.0910 Hom.: 2696

Bravo AF: 0.0906

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.0445 AC: 196

ESP6500EA AF: 0.0887 AC: 763

ExAC AF: 0.106 AC: 12860

Asia WGS AF: 0.133 AC: 461 AN: 3478

EpiCase AF: 0.0862

EpiControl AF: 0.0855

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Pyridoxine-dependent epilepsy (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.076
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.32
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.23
MPC		0.17
ClinPred		0.025	T
GERP RS		3.5
Varity_R		0.46
gMVP		0.68
Mutation Taster		=66/34	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.0020
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: rs12514417; hg19: chr5-125887715; COSMIC: COSV63160732; COSMIC: COSV63160732;