chr5-126593345-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001182.5(ALDH7A1):c.246+6A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 112,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000042 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ALDH7A1
NM_001182.5 splice_region, intron

Scores

Splicing: ADA: 0.00001031

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0930

Publications

0 publications found

Variant links:

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

ALDH7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 5-126593345-T-A is Benign according to our data. Variant chr5-126593345-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465327.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ALDH7A1	NM_001182.5 link	c.246+6A>T	splice_region_variant, intron_variant	Intron 2 of 17	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2 link	c.162+6A>T	splice_region_variant, intron_variant	Intron 2 of 17		NP_001188306.1
ALDH7A1	NM_001202404.2 link	c.246+6A>T	splice_region_variant, intron_variant	Intron 2 of 15		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 link	c.246+6A>T		splice_region_variant, intron_variant	Intron 2 of 17	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes

AF:

0.000187

AC:

AN:

112374

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000115

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000109

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000241

AC:

AN:

220354

AF XY:

0.000193

show subpopulations

Gnomad AFR exome

AF:

0.00107

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000221

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000436

Gnomad NFE exome

AF:

0.000270

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000419

AC:

AN:

1407128

Hom.:

Cov.:

AF XY:

0.0000357

AC XY:

AN XY:

700302

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000168

AC:

AN:

29836

American (AMR)

AF:

0.0000234

AC:

AN:

42652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25028

East Asian (EAS)

AF:

0.0000260

AC:

AN:

38458

South Asian (SAS)

AF:

0.0000485

AC:

AN:

82518

European-Finnish (FIN)

AF:

0.000317

AC:

AN:

50512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4824

European-Non Finnish (NFE)

AF:

0.0000288

AC:

AN:

1075308

Other (OTH)

AF:

0.0000172

AC:

AN:

57992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.287

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000187

AC:

AN:

112454

Hom.:

Cov.:

AF XY:

0.000128

AC XY:

AN XY:

54896

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

24574

American (AMR)

AF:

0.0000862

AC:

AN:

11600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2798

East Asian (EAS)

AF:

0.00

AC:

AN:

3776

South Asian (SAS)

AF:

0.00

AC:

AN:

3498

European-Finnish (FIN)

AF:

0.000115

AC:

AN:

8684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

204

European-Non Finnish (NFE)

AF:

0.000109

AC:

AN:

55120

Other (OTH)

AF:

0.00

AC:

AN:

1564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.406

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000838

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Uncertain:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 2 of the ALDH7A1 gene. It does not directly change the encoded amino acid sequence of the ALDH7A1 protein. It affects a nucleotide within the consensus splice site. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 465327). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Benign:1

Dec 21, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

1.7

(source)

DANN

Benign

0.80

PhyloP100

-0.093

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000010

dbscSNV1_RF

Benign

0.0040

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over