rs2230708

Positions:

• chr1-18875462-A-G
• chr1-18875462-A-T

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.1380T>C​(p.Asp460=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.724 in 1,613,800 control chromosomes in the GnomAD database, including 423,345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (38916 hom., cov: 31)
  • Exomes 𝑓: 0.72 (384429 hom.)
• Consequence: ALDH4A1 NM_003748.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.31

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=-0.89).
• BP6: Variant 1-18875462-A-G is Benign according to our data. Variant chr1-18875462-A-G is described in ClinVar as [Benign]. Clinvar id is 294369.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875462-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1380T>C	p.Asp460=	synonymous_variant	13/15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1380T>C	p.Asp460=	synonymous_variant	13/16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1227T>C	p.Asp409=	synonymous_variant	12/14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1200T>C	p.Asp400=	synonymous_variant	13/15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1380T>C	p.Asp460=	synonymous_variant	13/15	1	NM_003748.4	ENSP00000364490	P1
ALDH4A1	ENST00000290597.9	c.1380T>C	p.Asp460=	synonymous_variant	13/16	1		ENSP00000290597	P1
ALDH4A1	ENST00000538839.5	c.1227T>C	p.Asp409=	synonymous_variant	12/14	1		ENSP00000446071
ALDH4A1	ENST00000538309.5	c.1200T>C	p.Asp400=	synonymous_variant	13/15	2		ENSP00000442988

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108516 AN: 151872 Hom.: 38866 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.788

Gnomad AMR AF: 0.792

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.722

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.715

Gnomad OTH AF: 0.734

GnomAD3 exomes AF: 0.732 AC: 184101 AN: 251454 Hom.: 67767 AF XY: 0.732 AC XY: 99477 AN XY: 135908

Gnomad AFR exome AF: 0.688

Gnomad AMR exome AF: 0.818

Gnomad ASJ exome AF: 0.719

Gnomad EAS exome AF: 0.711

Gnomad SAS exome AF: 0.758

Gnomad FIN exome AF: 0.682

Gnomad NFE exome AF: 0.719

Gnomad OTH exome AF: 0.744

GnomAD4 exome AF: 0.725 AC: 1059164 AN: 1461810 Hom.: 384429 Cov.: 67 AF XY: 0.725 AC XY: 527322 AN XY: 727222

Gnomad4 AFR exome AF: 0.679

Gnomad4 AMR exome AF: 0.820

Gnomad4 ASJ exome AF: 0.722

Gnomad4 EAS exome AF: 0.727

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.683

Gnomad4 NFE exome AF: 0.722

Gnomad4 OTH exome AF: 0.718

GnomAD4 genome AF: 0.715 AC: 108625 AN: 151990 Hom.: 38916 Cov.: 31 AF XY: 0.716 AC XY: 53175 AN XY: 74296

Gnomad4 AFR AF: 0.685

Gnomad4 AMR AF: 0.792

Gnomad4 ASJ AF: 0.719

Gnomad4 EAS AF: 0.722

Gnomad4 SAS AF: 0.765

Gnomad4 FIN AF: 0.675

Gnomad4 NFE AF: 0.716

Gnomad4 OTH AF: 0.735

Alfa AF: 0.720 Hom.: 54845

Bravo AF: 0.723

Asia WGS AF: 0.732 AC: 2549 AN: 3478

EpiCase AF: 0.730

EpiControl AF: 0.733

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	- -

not specified Benign:2

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

not provided Benign:1

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	-0.89
CADD	Benign	0.030
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs2230708; hg19: chr1-19201956;