rs2230709

Variant names:

• chr1-18875434-C-T
• rs2230709
• NM_003748.4:c.1408G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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:4
• Conservation: PhyloP100: 2.20
• Publications: 22 publications found

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]

ALDH4A1 Gene-Disease associations (from GenCC):

• hyperprolinemia type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4	c.1408G>A	p.Val470Ile	missense_variant	Exon 13 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3	c.1408G>A	p.Val470Ile	missense_variant	Exon 13 of 16		NP_733844.1
ALDH4A1	NM_001319218.2	c.1255G>A	p.Val419Ile	missense_variant	Exon 12 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2	c.1228G>A	p.Val410Ile	missense_variant	Exon 13 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8	c.1408G>A	p.Val470Ile	missense_variant	Exon 13 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9	c.1408G>A	p.Val470Ile	missense_variant	Exon 13 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5	c.1255G>A	p.Val419Ile	missense_variant	Exon 12 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5	c.1228G>A	p.Val410Ile	missense_variant	Exon 13 of 15	2		ENSP00000442988.1

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

GnomAD2 exomes AF: 0.105 AC: 26338 AN: 251474 AF XY: 0.105

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 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

African (AFR) AF: 0.0343 AC: 1149 AN: 33480

American (AMR) AF: 0.0461 AC: 2063 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0551 AC: 1441 AN: 26136

East Asian (EAS) AF: 0.000353 AC: 14 AN: 39700

South Asian (SAS) AF: 0.0409 AC: 3525 AN: 86258

European-Finnish (FIN) AF: 0.230 AC: 12292 AN: 53410

Middle Eastern (MID) AF: 0.0392 AC: 226 AN: 5768

European-Non Finnish (NFE) AF: 0.148 AC: 165062 AN: 1111982

Other (OTH) AF: 0.117 AC: 7080 AN: 60396

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

African (AFR) AF: 0.0376 AC: 1563 AN: 41552

American (AMR) AF: 0.0756 AC: 1157 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5170

South Asian (SAS) AF: 0.0353 AC: 170 AN: 4818

European-Finnish (FIN) AF: 0.244 AC: 2587 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10300 AN: 67988

Other (OTH) AF: 0.0829 AC: 175 AN: 2110

Alfa AF: 0.128 Hom.: 3551

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperprolinemia type 2 Benign:2

Jan 12, 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 provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ALDH4A1-related disorder Benign:1

Nov 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.98	.;D;D;D
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N;.;N;.
PhyloP100		2.2
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
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

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