rs6695033

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003748.4(ALDH4A1):c.1417A>G(p.Thr473Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0282 in 1,614,048 control chromosomes in the GnomAD database, including 1,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T473N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 588 hom., cov: 33)

Exomes 𝑓: 0.025 ( 915 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.54

Publications

16 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: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics

ALDH4A1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003748.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016415417).

BP6

Variant 1-18875425-T-C is Benign according to our data. Variant chr1-18875425-T-C is described in ClinVar as Benign. ClinVar VariationId is 294366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003748.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH4A1	NM_003748.4	MANE Select	c.1417A>G	p.Thr473Ala	missense	Exon 13 of 15	NP_003739.2
ALDH4A1	NM_170726.3		c.1417A>G	p.Thr473Ala	missense	Exon 13 of 16	NP_733844.1	P30038-1
ALDH4A1	NM_001319218.2		c.1264A>G	p.Thr422Ala	missense	Exon 12 of 14	NP_001306147.1	P30038-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ALDH4A1	ENST00000375341.8	TSL:1 MANE Select	c.1417A>G	p.Thr473Ala	missense	Exon 13 of 15	ENSP00000364490.3	P30038-1
ALDH4A1	ENST00000290597.9	TSL:1	c.1417A>G	p.Thr473Ala	missense	Exon 13 of 16	ENSP00000290597.5	P30038-1
ALDH4A1	ENST00000538839.5	TSL:1	c.1264A>G	p.Thr422Ala	missense	Exon 12 of 14	ENSP00000446071.1	P30038-3

Frequencies

GnomAD3 genomes

AF:

0.0617

AC:

9375

AN:

152066

Hom.:

586

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0372

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.0235

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0224

Gnomad OTH

AF:

0.0527

GnomAD2 exomes

AF:

0.0310

AC:

7787

AN:

251476

AF XY:

0.0287

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.0227

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0270

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0247

AC:

36180

AN:

1461864

Hom.:

915

Cov.:

AF XY:

0.0243

AC XY:

17647

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.166

AC:

5563

AN:

33476

American (AMR)

AF:

0.0239

AC:

1067

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

831

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0172

AC:

1485

AN:

86258

European-Finnish (FIN)

AF:

0.0268

AC:

1433

AN:

53414

Middle Eastern (MID)

AF:

0.0668

AC:

385

AN:

5766

European-Non Finnish (NFE)

AF:

0.0211

AC:

23420

AN:

1111996

Other (OTH)

AF:

0.0330

AC:

1995

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

2113

4227

6340

8454

10567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

954

1908

2862

3816

4770

<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:

0.0617

AC:

9392

AN:

152184

Hom.:

588

Cov.:

AF XY:

0.0595

AC XY:

4428

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.161

AC:

6693

AN:

41502

American (AMR)

AF:

0.0371

AC:

567

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.0187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0235

AC:

249

AN:

10618

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0224

AC:

1524

AN:

67988

Other (OTH)

AF:

0.0521

AC:

110

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

433

866

1300

1733

2166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

294

392

490

<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:

0.0342

Hom.:

927

Bravo

AF:

0.0676

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0278

EpiControl

AF:

0.0272

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperprolinemia type 2 (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Benign

0.60

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.15

Sift

Benign

0.11

Sift4G

Benign

0.068

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.30

gMVP

0.72

Mutation Taster

=29/71

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over