rs60720055

Positions:

• chr5-126592703-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000409134.8(ALDH7A1):​c.273T>C​(p.Thr91=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,613,936 control chromosomes in the GnomAD database, including 1,362 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (491 hom., cov: 32)
  • Exomes 𝑓: 0.024 (871 hom.)
• Consequence: ALDH7A1 ENST00000409134.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0950

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 5-126592703-A-G is Benign according to our data. Variant chr5-126592703-A-G is described in ClinVar as [Benign]. Clinvar id is 128347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126592703-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.095 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.144 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.273T>C	p.Thr91=	synonymous_variant	3/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.189T>C	p.Thr63=	synonymous_variant	3/18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.273T>C	p.Thr91=	synonymous_variant	3/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.273T>C	p.Thr91=	synonymous_variant	3/18	1	NM_001182.5	ENSP00000387123	P4

Frequencies

GnomAD3 genomes AF: 0.0585 AC: 8897 AN: 152168 Hom.: 491 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0556

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0273

Gnomad FIN AF: 0.00819

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0230

Gnomad OTH AF: 0.0502

GnomAD3 exomes AF: 0.0303 AC: 7606 AN: 251410 Hom.: 274 AF XY: 0.0283 AC XY: 3848 AN XY: 135874

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.0226

Gnomad ASJ exome AF: 0.0597

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0284

Gnomad FIN exome AF: 0.00975

Gnomad NFE exome AF: 0.0218

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0244 AC: 35628 AN: 1461650 Hom.: 871 Cov.: 30 AF XY: 0.0244 AC XY: 17750 AN XY: 727132

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.0249

Gnomad4 ASJ exome AF: 0.0609

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0284

Gnomad4 FIN exome AF: 0.00972

Gnomad4 NFE exome AF: 0.0205

Gnomad4 OTH exome AF: 0.0323

GnomAD4 genome AF: 0.0585 AC: 8916 AN: 152286 Hom.: 491 Cov.: 32 AF XY: 0.0563 AC XY: 4195 AN XY: 74458

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.0414

Gnomad4 ASJ AF: 0.0556

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0269

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.0230

Gnomad4 OTH AF: 0.0497

Alfa AF: 0.0398 Hom.: 173

Bravo AF: 0.0650

Asia WGS AF: 0.0240 AC: 83 AN: 3478

EpiCase AF: 0.0230

EpiControl AF: 0.0236

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 Diagnostics Laboratory, University Medical Center Utrecht	Jan 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.6
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: rs60720055; hg19: chr5-125928395;