rs57902950

Positions:

• chr5-126575440-G-A
• chr5-126575440-G-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001182.5(ALDH7A1):​c.675C>T​(p.Leu225=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00618 in 1,613,094 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (84 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (184 hom.)
• Consequence: ALDH7A1 NM_001182.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.65

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 5-126575440-G-A is Benign according to our data. Variant chr5-126575440-G-A is described in ClinVar as [Benign]. Clinvar id is 128349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126575440-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.65 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.675C>T	p.Leu225=	synonymous_variant	7/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.591C>T	p.Leu197=	synonymous_variant	7/18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.675C>T	p.Leu225=	synonymous_variant	7/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.675C>T	p.Leu225=	synonymous_variant	7/18	1	NM_001182.5	ENSP00000387123	P4

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2791 AN: 152026 Hom.: 83 Cov.: 32

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0484

Gnomad SAS AF: 0.0278

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000383

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.0121 AC: 3028 AN: 250542 Hom.: 83 AF XY: 0.0120 AC XY: 1618 AN XY: 135380

Gnomad AFR exome AF: 0.0573

Gnomad AMR exome AF: 0.00293

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.0548

Gnomad SAS exome AF: 0.0294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000458

Gnomad OTH exome AF: 0.00834

GnomAD4 exome AF: 0.00491 AC: 7177 AN: 1460950 Hom.: 184 Cov.: 30 AF XY: 0.00541 AC XY: 3929 AN XY: 726724

Gnomad4 AFR exome AF: 0.0567

Gnomad4 AMR exome AF: 0.00343

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0365

Gnomad4 SAS exome AF: 0.0293

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0184 AC: 2795 AN: 152144 Hom.: 84 Cov.: 32 AF XY: 0.0178 AC XY: 1322 AN XY: 74400

Gnomad4 AFR AF: 0.0546

Gnomad4 AMR AF: 0.00531

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0487

Gnomad4 SAS AF: 0.0276

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000383

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00462 Hom.: 17

Bravo AF: 0.0212

Asia WGS AF: 0.0610 AC: 210 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000890

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Pyridoxine-dependent epilepsy Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	9.1
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs57902950; hg19: chr5-125911132;