1-18885513-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003748.4(ALDH4A1):c.413C>T(p.Pro138Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,542,014 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P138P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0024 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0024 ( 4 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 6.21

Publications

5 publications found

Variant links:

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

ALDH4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009564936).

BP6

Variant 1-18885513-G-A is Benign according to our data. Variant chr1-18885513-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 294391.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00237 (347/146580) while in subpopulation AFR AF = 0.004 (160/40034). AF 95% confidence interval is 0.00349. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 16		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 14		NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2 link	c.233C>T	p.Pro78Leu	missense_variant	Exon 5 of 15		NP_001154976.1	P30038-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8 link	c.413C>T	p.Pro138Leu	missense_variant	Exon 5 of 15	1	NM_003748.4	ENSP00000364490.3		P30038-1

Frequencies

GnomAD3 genomes

AF:

0.00237

AC:

347

AN:

146464

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000415

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000228

Gnomad FIN

AF:

0.000624

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00258

Gnomad OTH

AF:

0.00147

GnomAD2 exomes

AF:

0.00128

AC:

286

AN:

223664

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.00272

Gnomad AMR exome

AF:

0.000217

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000913

Gnomad NFE exome

AF:

0.00214

Gnomad OTH exome

AF:

0.00177

GnomAD4 exome

AF:

0.00241

AC:

3359

AN:

1395434

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

1637

AN XY:

692414

show subpopulations

African (AFR)

AF:

0.00285

AC:

AN:

31596

American (AMR)

AF:

0.000293

AC:

AN:

41002

Ashkenazi Jewish (ASJ)

AF:

0.0000418

AC:

AN:

23902

East Asian (EAS)

AF:

0.00

AC:

AN:

35018

South Asian (SAS)

AF:

0.0000360

AC:

AN:

83380

European-Finnish (FIN)

AF:

0.00156

AC:

AN:

47940

Middle Eastern (MID)

AF:

0.000183

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00290

AC:

3105

AN:

1070962

Other (OTH)

AF:

0.00128

AC:

AN:

56174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

187

373

560

746

933

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00237

AC:

347

AN:

146580

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

151

AN XY:

71220

show subpopulations

African (AFR)

AF:

0.00400

AC:

160

AN:

40034

American (AMR)

AF:

0.000415

AC:

AN:

14466

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4664

South Asian (SAS)

AF:

0.000228

AC:

AN:

4390

European-Finnish (FIN)

AF:

0.000624

AC:

AN:

9614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00256

AC:

171

AN:

66752

Other (OTH)

AF:

0.00146

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00214

Hom.:

Bravo

AF:

0.00223

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Uncertain:1Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ALDH4A1: BP4 -

ALDH4A1-related disorder

Benign:1

Dec 01, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.38

T;.;T;.;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;D;D;D;D

MetaRNN

Benign

0.0096

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.9

M;M;M;.;.

PhyloP100

6.2

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.7

D;D;D;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0050

D;D;D;D;D

Sift4G

Uncertain

0.011

D;T;D;T;.

Polyphen

0.96

D;.;D;.;.

Vest4

0.57

MVP

0.54

MPC

0.11

ClinPred

0.10

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.57

Mutation Taster

=83/17

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over