rs12514417

chr5-126552023-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001182.5(ALDH7A1):c.1315A>C(p.Lys439Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0959 in 1,609,982 control chromosomes in the GnomAD database, including 8,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (711 hom., cov: 32)
  • Exomes 𝑓: 0.097 (7546 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense, splice_region
• Scores: Splicing: ADA: 0.0002109
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.92

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001182.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.00204584).
• BP6: Variant 5-126552023-T-G is Benign according to our data. Variant chr5-126552023-T-G is described in ClinVar as [Benign]. Clinvar id is 128346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126552023-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH7A1	NM_001182.5	c.1315A>C	p.Lys439Gln	missense_variant, splice_region_variant	14/18	ENST00000409134.8
ALDH7A1	NM_001201377.2	c.1231A>C	p.Lys411Gln	missense_variant, splice_region_variant	14/18
ALDH7A1	NM_001202404.2	c.1123A>C	p.Lys375Gln	missense_variant, splice_region_variant	12/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.1315A>C	p.Lys439Gln	missense_variant, splice_region_variant	14/18	1	NM_001182.5	P4

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13300 AN: 152114 Hom.: 705 Cov.: 32

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.0989

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.0812

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.0783

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0925

Gnomad OTH AF: 0.0765

GnomAD3 exomes AF: 0.114 AC: 28669 AN: 251026 Hom.: 2132 AF XY: 0.109 AC XY: 14722 AN XY: 135658

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.241

Gnomad ASJ exome AF: 0.0768

Gnomad EAS exome AF: 0.142

Gnomad SAS exome AF: 0.0789

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.0908

Gnomad OTH exome AF: 0.102

GnomAD4 exome AF: 0.0968 AC: 141066 AN: 1457750 Hom.: 7546 Cov.: 31 AF XY: 0.0956 AC XY: 69359 AN XY: 725456

Gnomad4 AFR exome AF: 0.0402

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.0752

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.0793

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.0930

Gnomad4 OTH exome AF: 0.0923

GnomAD4 genome AF: 0.0875 AC: 13322 AN: 152232 Hom.: 711 Cov.: 32 AF XY: 0.0893 AC XY: 6645 AN XY: 74430

Gnomad4 AFR AF: 0.0436

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.0812

Gnomad4 EAS AF: 0.151

Gnomad4 SAS AF: 0.0779

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.0925

Gnomad4 OTH AF: 0.0799

Alfa AF: 0.0912 Hom.: 1889

Bravo AF: 0.0906

TwinsUK AF: 0.0965 AC: 358

ALSPAC AF: 0.0893 AC: 344

ESP6500AA AF: 0.0445 AC: 196

ESP6500EA AF: 0.0887 AC: 763

ExAC AF: 0.106 AC: 12860

Asia WGS AF: 0.133 AC: 461 AN: 3478

EpiCase AF: 0.0862

EpiControl AF: 0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2013	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Pyridoxine-dependent epilepsy Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 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
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.032	T;T;T;.;T;.;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.076
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.68	T;T;T;T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	0.90	P;P;P
PrimateAI	Uncertain	0.54	T
Polyphen		0.0010	.;B;.;.;.;.;.;.
Vest4		0.23, 0.20
MPC		0.17
ClinPred		0.025	T
GERP RS		3.5
Varity_R		0.46
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00021
dbscSNV1_RF	Benign	0.0020
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: rs12514417; hg19: chr5-125887715; COSMIC: COSV63160732; COSMIC: COSV63160732;