5-126545018-T-C

Variant names:

• chr5-126545018-T-C
• rs61757684
• NM_001182.5:c.1567A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001182.5(ALDH7A1):​c.1567A>G​(p.Thr523Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00544 in 1,604,892 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (25 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense, splice_region
• Scores: Splicing: ADA: 0.7900
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 6.90
• Publications: 10 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: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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=0.015203327).
• BP6: Variant 5-126545018-T-C is Benign according to our data. Variant chr5-126545018-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00395 (601/152336) while in subpopulation NFE AF = 0.0055 (374/68034). AF 95% confidence interval is 0.00504. There are 3 homozygotes in GnomAd4. There are 294 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	NM_001182.5	MANE Select	c.1567A>G	p.Thr523Ala	missense splice_region	Exon 18 of 18	NP_001173.2
	ALDH7A1	NM_001201377.2		c.1483A>G	p.Thr495Ala	missense splice_region	Exon 18 of 18	NP_001188306.1
	ALDH7A1	NM_001202404.2		c.1375A>G	p.Thr459Ala	missense splice_region	Exon 16 of 16	NP_001189333.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.1567A>G	p.Thr523Ala	missense splice_region	Exon 18 of 18	ENSP00000387123.3
	ALDH7A1	ENST00000636879.1	TSL:5	c.1612A>G	p.Thr538Ala	missense splice_region	Exon 19 of 19	ENSP00000490811.1
	ALDH7A1	ENST00000637272.1	TSL:5	c.1558A>G	p.Thr520Ala	missense splice_region	Exon 18 of 18	ENSP00000489686.1

Frequencies

GnomAD3 genomes AF: 0.00395 AC: 601 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00448 AC: 1124 AN: 251000 AF XY: 0.00454

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00981

Gnomad NFE exome AF: 0.00529

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00560 AC: 8132 AN: 1452556 Hom.: 25 Cov.: 29 AF XY: 0.00536 AC XY: 3875 AN XY: 723232

African (AFR) AF: 0.00120 AC: 40 AN: 33278

American (AMR) AF: 0.00134 AC: 60 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 293 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00378 AC: 325 AN: 86066

European-Finnish (FIN) AF: 0.0102 AC: 546 AN: 53376

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5744

European-Non Finnish (NFE) AF: 0.00597 AC: 6588 AN: 1103626

Other (OTH) AF: 0.00456 AC: 274 AN: 60092

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74496

African (AFR) AF: 0.000938 AC: 39 AN: 41580

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

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

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0103 AC: 109 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68034

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00481 Hom.: 7

Bravo AF: 0.00330

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00448 AC: 544

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00427

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Pyridoxine-dependent epilepsy (6)
-	-	5	not provided (5)
-	-	4	not specified (4)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.0	L
PhyloP100		6.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.78
MVP		0.83
MPC		0.65
ClinPred		0.019	T
GERP RS		4.8
Varity_R		0.90
gMVP		0.86
Mutation Taster		=11/89	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.48
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: rs61757684; hg19: chr5-125880710; COSMIC: COSV99072286; COSMIC: COSV99072286;