1-18876423-T-C

Position:

• chr1-18876423-T-C

Variant summary

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

The ENST00000375341.8(ALDH4A1):​c.1230A>G​(p.Ser410=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,608,858 control chromosomes in the GnomAD database, including 391,287 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31993 hom., cov: 32)
  • Exomes 𝑓: 0.70 (359294 hom.)
• Consequence: ALDH4A1 ENST00000375341.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -6.07

Genes affected

ALDH4A1 (HGNC:406): (aldehyde dehydrogenase 4 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-18876423-T-C is Benign according to our data. Variant chr1-18876423-T-C is described in ClinVar as [Benign]. Clinvar id is 294375.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18876423-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.07 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1230A>G	p.Ser410=	synonymous_variant	12/15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1230A>G	p.Ser410=	synonymous_variant	12/16		NP_733844.1
ALDH4A1	NM_001161504.2	c.1050A>G	p.Ser350=	synonymous_variant	12/15		NP_001154976.1
ALDH4A1	NM_001319218.2	c.1185+785A>G		intron_variant			NP_001306147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1230A>G	p.Ser410=	synonymous_variant	12/15	1	NM_003748.4	ENSP00000364490	P1
ALDH4A1	ENST00000290597.9	c.1230A>G	p.Ser410=	synonymous_variant	12/16	1		ENSP00000290597	P1
ALDH4A1	ENST00000538839.5	c.1185+785A>G		intron_variant		1		ENSP00000446071
ALDH4A1	ENST00000538309.5	c.1050A>G	p.Ser350=	synonymous_variant	12/15	2		ENSP00000442988

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97343 AN: 151436 Hom.: 31974 Cov.: 32

Gnomad AFR AF: 0.486

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.679

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.695

Gnomad OTH AF: 0.678

GnomAD3 exomes AF: 0.699 AC: 170871 AN: 244574 Hom.: 60119 AF XY: 0.701 AC XY: 92938 AN XY: 132564

Gnomad AFR exome AF: 0.484

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.712

Gnomad SAS exome AF: 0.742

Gnomad FIN exome AF: 0.651

Gnomad NFE exome AF: 0.695

Gnomad OTH exome AF: 0.711

GnomAD4 exome AF: 0.701 AC: 1021107 AN: 1457304 Hom.: 359294 Cov.: 56 AF XY: 0.702 AC XY: 508675 AN XY: 724836

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.796

Gnomad4 ASJ exome AF: 0.691

Gnomad4 EAS exome AF: 0.729

Gnomad4 SAS exome AF: 0.738

Gnomad4 FIN exome AF: 0.654

Gnomad4 NFE exome AF: 0.703

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.643 AC: 97417 AN: 151554 Hom.: 31993 Cov.: 32 AF XY: 0.646 AC XY: 47826 AN XY: 74026

Gnomad4 AFR AF: 0.486

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.679

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.695

Gnomad4 OTH AF: 0.679

Alfa AF: 0.659 Hom.: 6167

Bravo AF: 0.644

Asia WGS AF: 0.707 AC: 2460 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:3

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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.091
DANN	Benign	0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs7550938; hg19: chr1-19202917; COSMIC: COSV51894187;