rs1270423610

Variant names:

• chr5-126568334-G-A
• rs1270423610
• NM_001182.5:c.796C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-126568334-G-A
• chr5-126568334-G-C
• chr5-126568334-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001182.5(ALDH7A1):​c.796C>T​(p.Arg266*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000116 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.11
• Publications: 4 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: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-126568334-G-A is Pathogenic according to our data. Variant chr5-126568334-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 465333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.796C>T	p.Arg266*	stop_gained	Exon 9 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.712C>T	p.Arg238*	stop_gained	Exon 9 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.796C>T	p.Arg266*	stop_gained	Exon 9 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.796C>T	p.Arg266*	stop_gained	Exon 9 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.841C>T	p.Arg281*	stop_gained	Exon 10 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.796C>T	p.Arg266*	stop_gained	Exon 9 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251476 AF XY: 0.00000736

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727200

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111934

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.1
Vest4		0.92
GERP RS		4.3
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.36		Position offset: 22

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

Other links and lift over

dbSNP: rs1270423610; hg19: chr5-125904026; COSMIC: COSV68629131;