1-18872954-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_003748.4(ALDH4A1):c.1583C>A(p.Thr528Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,613,640 control chromosomes in the GnomAD database, including 484 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.017 ( 38 hom., cov: 33)

Exomes 𝑓: 0.023 ( 446 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 9.74

Publications

15 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 -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.01019305).

BP6

Variant 1-18872954-G-T is Benign according to our data. Variant chr1-18872954-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471329.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0169 (2571/152308) while in subpopulation NFE AF = 0.0252 (1715/68024). AF 95% confidence interval is 0.0242. There are 38 homozygotes in GnomAd4. There are 1267 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 16		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.1430C>A	p.Thr477Asn	missense_variant	Exon 14 of 14		NP_001306147.1	P30038-3
ALDH4A1	NM_001161504.2 link	c.1403C>A	p.Thr468Asn	missense_variant	Exon 15 of 15		NP_001154976.1	P30038-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALDH4A1	ENST00000375341.8 link	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 15	1	NM_003748.4	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9 link	c.1583C>A	p.Thr528Asn	missense_variant	Exon 15 of 16	1		ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5 link	c.1430C>A	p.Thr477Asn	missense_variant	Exon 14 of 14	1		ENSP00000446071.1	P30038-3
ALDH4A1	ENST00000538309.5 link	c.1403C>A	p.Thr468Asn	missense_variant	Exon 15 of 15	2		ENSP00000442988.1	P30038-2

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2572

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00405

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.00942

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00165

Gnomad FIN

AF:

0.0426

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0252

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0168

AC:

4216

AN:

251076

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.00370

Gnomad AMR exome

AF:

0.00630

Gnomad ASJ exome

AF:

0.0101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0393

Gnomad NFE exome

AF:

0.0248

Gnomad OTH exome

AF:

0.0179

GnomAD4 exome

AF:

0.0230

AC:

33593

AN:

1461332

Hom.:

446

Cov.:

AF XY:

0.0223

AC XY:

16234

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00314

AC:

105

AN:

33474

American (AMR)

AF:

0.00642

AC:

287

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

279

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00184

AC:

159

AN:

86252

European-Finnish (FIN)

AF:

0.0383

AC:

2037

AN:

53148

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0267

AC:

29658

AN:

1111758

Other (OTH)

AF:

0.0173

AC:

1045

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1500

3000

4500

6000

7500

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1106

2212

3318

4424

5530

<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:

0.0169

AC:

2571

AN:

152308

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

1267

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.00404

AC:

168

AN:

41562

American (AMR)

AF:

0.00941

AC:

144

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00166

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0426

AC:

453

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0252

AC:

1715

AN:

68024

Other (OTH)

AF:

0.0114

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

132

263

395

526

658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0214

Hom.:

132

Bravo

AF:

0.0140

TwinsUK

AF:

0.0254

AC:

ALSPAC

AF:

0.0280

AC:

108

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.0243

AC:

209

ExAC

AF:

0.0167

AC:

2024

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0209

EpiControl

AF:

0.0209

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

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 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.57

D;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D;D;D

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Pathogenic

4.2

H;.;H;.

PhyloP100

9.7

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D

Polyphen

1.0

D;.;D;.

Vest4

0.76

MPC

0.43

ClinPred

0.057

GERP RS

4.8

Varity_R

0.84

gMVP

0.78

Mutation Taster

=71/29

polymorphism (auto)

(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