1-18876432-T-C

Variant names:

• chr1-18876432-T-C
• rs2230706
• NM_003748.4:c.1221A>G

Variant summary

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

The NM_003748.4(ALDH4A1):​c.1221A>G​(p.Ala407Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,606,196 control chromosomes in the GnomAD database, including 389,798 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31953 hom., cov: 32)
  • Exomes 𝑓: 0.70 (357845 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.128

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=-0.53).
• BP6: Variant 1-18876432-T-C is Benign according to our data. Variant chr1-18876432-T-C is described in ClinVar as [Benign]. Clinvar id is 294376.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18876432-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1221A>G	p.Ala407Ala	synonymous_variant	Exon 12 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1221A>G	p.Ala407Ala	synonymous_variant	Exon 12 of 16		NP_733844.1
ALDH4A1	NM_001161504.2	c.1041A>G	p.Ala347Ala	synonymous_variant	Exon 12 of 15		NP_001154976.1
ALDH4A1	NM_001319218.2	c.1185+776A>G		intron_variant	Intron 11 of 13		NP_001306147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1221A>G	p.Ala407Ala	synonymous_variant	Exon 12 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1221A>G	p.Ala407Ala	synonymous_variant	Exon 12 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1185+776A>G		intron_variant	Intron 11 of 13	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1041A>G	p.Ala347Ala	synonymous_variant	Exon 12 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97277 AN: 151480 Hom.: 31934 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.750

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.720

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.650

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.677

GnomAD3 exomes AF: 0.698 AC: 167755 AN: 240402 Hom.: 58897 AF XY: 0.700 AC XY: 91392 AN XY: 130544

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.794

Gnomad ASJ exome AF: 0.690

Gnomad EAS exome AF: 0.710

Gnomad SAS exome AF: 0.742

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.693

Gnomad OTH exome AF: 0.709

GnomAD4 exome AF: 0.700 AC: 1018100 AN: 1454598 Hom.: 357845 Cov.: 56 AF XY: 0.701 AC XY: 507140 AN XY: 723398

Gnomad4 AFR exome AF: 0.474

Gnomad4 AMR exome AF: 0.795

Gnomad4 ASJ exome AF: 0.692

Gnomad4 EAS exome AF: 0.727

Gnomad4 SAS exome AF: 0.737

Gnomad4 FIN exome AF: 0.653

Gnomad4 NFE exome AF: 0.702

Gnomad4 OTH exome AF: 0.684

GnomAD4 genome AF: 0.642 AC: 97351 AN: 151598 Hom.: 31953 Cov.: 32 AF XY: 0.645 AC XY: 47792 AN XY: 74048

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.751

Gnomad4 ASJ AF: 0.680

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.747

Gnomad4 FIN AF: 0.650

Gnomad4 NFE AF: 0.694

Gnomad4 OTH AF: 0.678

Alfa AF: 0.687 Hom.: 21298

Bravo AF: 0.644

Asia WGS AF: 0.706 AC: 2458 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:3

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Apr 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.62
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2230706; hg19: chr1-19202926; COSMIC: COSV51893163;