rs2230709

chr1-18875434-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003748.4(ALDH4A1):c.1408G>A(p.Val470Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,614,076 control chromosomes in the GnomAD database, including 15,735 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1232 hom., cov: 33)
  • Exomes 𝑓: 0.13 (14503 hom.)
• Consequence: ALDH4A1 NM_003748.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.20

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017163455).
• BP6: Variant 1-18875434-C-T is Benign according to our data. Variant chr1-18875434-C-T is described in ClinVar as [Benign]. Clinvar id is 294367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH4A1	NM_003748.4	c.1408G>A	p.Val470Ile	missense_variant	13/15	ENST00000375341.8
ALDH4A1	NM_170726.3	c.1408G>A	p.Val470Ile	missense_variant	13/16
ALDH4A1	NM_001319218.2	c.1255G>A	p.Val419Ile	missense_variant	12/14
ALDH4A1	NM_001161504.2	c.1228G>A	p.Val410Ile	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1408G>A	p.Val470Ile	missense_variant	13/15	1	NM_003748.4	P1
ALDH4A1	ENST00000290597.9	c.1408G>A	p.Val470Ile	missense_variant	13/16	1		P1
ALDH4A1	ENST00000538839.5	c.1255G>A	p.Val419Ile	missense_variant	12/14	1
ALDH4A1	ENST00000538309.5	c.1228G>A	p.Val410Ile	missense_variant	13/15	2

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16218 AN: 152106 Hom.: 1233 Cov.: 33

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.0838

GnomAD3 exomes AF: 0.105 AC: 26338 AN: 251474 Hom.: 2033 AF XY: 0.105 AC XY: 14252 AN XY: 135916

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.0452

Gnomad ASJ exome AF: 0.0519

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.0389

Gnomad FIN exome AF: 0.232

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.132 AC: 192852 AN: 1461852 Hom.: 14503 Cov.: 33 AF XY: 0.129 AC XY: 94110 AN XY: 727224

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.0551

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0409

Gnomad4 FIN exome AF: 0.230

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.117

GnomAD4 genome AF: 0.107 AC: 16214 AN: 152224 Hom.: 1232 Cov.: 33 AF XY: 0.109 AC XY: 8093 AN XY: 74428

Gnomad4 AFR AF: 0.0376

Gnomad4 AMR AF: 0.0756

Gnomad4 ASJ AF: 0.0524

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.0353

Gnomad4 FIN AF: 0.244

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.0829

Alfa AF: 0.130 Hom.: 2642

Bravo AF: 0.0900

TwinsUK AF: 0.146 AC: 540

ALSPAC AF: 0.143 AC: 552

ESP6500AA AF: 0.0411 AC: 181

ESP6500EA AF: 0.148 AC: 1276

ExAC AF: 0.104 AC: 12671

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.127

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

ALDH4A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.074	T;.;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.23	N
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;.;N;.
MutationTaster	Benign	0.00028	P;P;P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.25	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.28	T;T;T;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.031	B;.;B;.
Vest4		0.13
MPC		0.084
ClinPred		0.012	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.21
gMVP		0.32

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: rs2230709; hg19: chr1-19201928; COSMIC: COSV51892342;