5-126595136-A-G

Position:

• chr5-126595136-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_001182.5(ALDH7A1):​c.63T>C​(p.Pro21=) variant causes a synonymous 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_001182.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0300

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 287061.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.03 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.63T>C	p.Pro21=	synonymous_variant	1/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001202404.2	c.63T>C	p.Pro21=	synonymous_variant	1/16		NP_001189333.2
ALDH7A1	NM_001201377.2	c.-22T>C		5_prime_UTR_variant	1/18		NP_001188306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.63T>C	p.Pro21=	synonymous_variant	1/18	1	NM_001182.5	ENSP00000387123	P4

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

GnomAD3 exomes AF: 0.000143 AC: 25 AN: 175394 Hom.: 0 AF XY: 0.000118 AC XY: 11 AN XY: 93538

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 SAS 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

Gnomad4 AFR exome AF: 0.0000937

Gnomad4 AMR exome AF: 0.0000785

Gnomad4 ASJ exome AF: 0.0000394

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000194

Gnomad4 OTH exome AF: 0.0000341

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	ALDH7A1: BP4, BP7 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 19, 2016	- -

Pyridoxine-dependent epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.2
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs368427726; hg19: chr5-125930828;