5-126595136-A-G

Variant names:

• chr5-126595136-A-G
• rs368427726
• NM_001182.5:c.63T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_001201377.2(ALDH7A1):​c.-22T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,567,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: ALDH7A1 NM_001201377.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0300
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-126595136-A-G is Benign according to our data. Variant chr5-126595136-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287061.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201377.2. 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.63T>C	p.Pro21Pro	synonymous	Exon 1 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.-22T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.63T>C	p.Pro21Pro	synonymous	Exon 1 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.63T>C	p.Pro21Pro	synonymous	Exon 1 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.63T>C	p.Pro21Pro	synonymous	Exon 1 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.63T>C	p.Pro21Pro	synonymous	Exon 1 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152204 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000235

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000143 AC: 25 AN: 175394 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000267

Gnomad OTH exome AF: 0.000423

GnomAD4 exome AF: 0.000160 AC: 226 AN: 1415354 Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 118 AN XY: 699898

African (AFR) AF: 0.0000937 AC: 3 AN: 32030

American (AMR) AF: 0.0000785 AC: 3 AN: 38214

Ashkenazi Jewish (ASJ) AF: 0.0000394 AC: 1 AN: 25406

East Asian (EAS) AF: 0.00 AC: 0 AN: 36888

South Asian (SAS) AF: 0.00 AC: 0 AN: 80676

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50276

Middle Eastern (MID) AF: 0.00105 AC: 6 AN: 5718

European-Non Finnish (NFE) AF: 0.000194 AC: 211 AN: 1087536

Other (OTH) AF: 0.0000341 AC: 2 AN: 58610

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152204 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.000196 AC: 3 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Pyridoxine-dependent epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.2
DANN	Benign	0.71
PhyloP100		0.030
PromoterAI		-0.045	Neutral
Mutation Taster		=97/3	polymorphism

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: rs368427726; hg19: chr5-125930828;