rs146450609

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.47C>T(p.Pro16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,449,494 control chromosomes in the GnomAD database, including 689 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 54 hom., cov: 32)

Exomes 𝑓: 0.029 ( 635 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.56

Publications

9 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:

ENSG00000310349 (HGNC:):

ENSG00000310349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.004030764).

BP6

Variant 1-18902477-G-A is Benign according to our data. Variant chr1-18902477-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 471330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH4A1	NM_003748.4 link	c.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 15	ENST00000375341.8	NP_003739.2	P30038-1A0A024RAC7
ALDH4A1	NM_170726.3 link	c.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 16		NP_733844.1	P30038-1A0A024RAC7
ALDH4A1	NM_001319218.2 link	c.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 14		NP_001306147.1	P30038-3
LOC124903866	XR_007065519.1 link	n.140+225G>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8 link	c.47C>T	p.Pro16Leu	missense_variant	Exon 1 of 15	1	NM_003748.4	ENSP00000364490.3		P30038-1

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3726

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0103

Gnomad AMI

AF:

0.0241

Gnomad AMR

AF:

0.0301

Gnomad ASJ

AF:

0.0438

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.0394

Gnomad MID

AF:

0.0573

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0349

GnomAD2 exomes

AF:

0.0185

AC:

1464

AN:

79020

AF XY:

0.0185

show subpopulations

Gnomad AFR exome

AF:

0.00797

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0243

Gnomad OTH exome

AF:

0.0315

GnomAD4 exome

AF:

0.0288

AC:

37361

AN:

1297244

Hom.:

635

Cov.:

AF XY:

0.0285

AC XY:

18171

AN XY:

637704

show subpopulations

African (AFR)

AF:

0.0106

AC:

288

AN:

27070

American (AMR)

AF:

0.0197

AC:

533

AN:

27010

Ashkenazi Jewish (ASJ)

AF:

0.0330

AC:

737

AN:

22332

East Asian (EAS)

AF:

0.0000342

AC:

AN:

29282

South Asian (SAS)

AF:

0.0117

AC:

803

AN:

68710

European-Finnish (FIN)

AF:

0.0311

AC:

984

AN:

31624

Middle Eastern (MID)

AF:

0.0604

AC:

309

AN:

5112

European-Non Finnish (NFE)

AF:

0.0311

AC:

32081

AN:

1032516

Other (OTH)

AF:

0.0303

AC:

1625

AN:

53588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

1739

3479

5218

6958

8697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1282

2564

3846

5128

6410

<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:

0.0244

AC:

3720

AN:

152250

Hom.:

Cov.:

AF XY:

0.0252

AC XY:

1872

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0102

AC:

424

AN:

41574

American (AMR)

AF:

0.0301

AC:

460

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0438

AC:

152

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5156

South Asian (SAS)

AF:

0.0110

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0394

AC:

418

AN:

10604

Middle Eastern (MID)

AF:

0.0582

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0309

AC:

2100

AN:

67994

Other (OTH)

AF:

0.0345

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

196

391

587

782

978

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0260

Hom.:

Bravo

AF:

0.0242

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0337

AC:

130

ExAC

AF:

0.00907

AC:

204

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperprolinemia type 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 31, 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.022

T;.;T;.

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.75

.;T;T;T

MetaRNN

Benign

0.0040

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;L;L;.

PhyloP100

1.6

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.070

N;N;N;N

REVEL

Benign

0.15

Sift

Benign

0.072

T;T;T;D

Sift4G

Benign

0.13

T;T;T;.

Polyphen

0.018

B;.;B;.

Vest4

0.23

MPC

0.10

ClinPred

0.019

GERP RS

3.4

PromoterAI

0.092

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.036

gMVP

0.40

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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