1-18877231-A-G

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.1162T>C(p.Phe388Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0163 in 1,608,354 control chromosomes in the GnomAD database, including 281 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 16 hom., cov: 32)

Exomes 𝑓: 0.017 ( 265 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.43

Publications

13 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0095697045).

BP6

Variant 1-18877231-A-G is Benign according to our data. Variant chr1-18877231-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALDH4A1	NM_003748.4 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 16		NP_733844.1
ALDH4A1	NM_001319218.2 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2 link	c.982T>C	p.Phe328Leu	missense_variant	Exon 11 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ALDH4A1	ENST00000375341.8 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 15	1	NM_003748.4	ENSP00000364490.3
ALDH4A1	ENST00000290597.9 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 16	1		ENSP00000290597.5
ALDH4A1	ENST00000538839.5 link	c.1162T>C	p.Phe388Leu	missense_variant	Exon 11 of 14	1		ENSP00000446071.1
ALDH4A1	ENST00000538309.5 link	c.982T>C	p.Phe328Leu	missense_variant	Exon 11 of 15	2		ENSP00000442988.1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2064

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00294

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0142

Gnomad ASJ

AF:

0.0360

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.0184

Gnomad FIN

AF:

0.0224

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0180

Gnomad OTH

AF:

0.0153

GnomAD2 exomes

AF:

0.0164

AC:

3932

AN:

240130

AF XY:

0.0173

show subpopulations

Gnomad AFR exome

AF:

0.00290

Gnomad AMR exome

AF:

0.0129

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.000668

Gnomad FIN exome

AF:

0.0247

Gnomad NFE exome

AF:

0.0189

Gnomad OTH exome

AF:

0.0243

GnomAD4 exome

AF:

0.0166

AC:

24156

AN:

1456092

Hom.:

265

Cov.:

AF XY:

0.0169

AC XY:

12212

AN XY:

723694

show subpopulations

African (AFR)

AF:

0.00424

AC:

141

AN:

33242

American (AMR)

AF:

0.0127

AC:

563

AN:

44336

Ashkenazi Jewish (ASJ)

AF:

0.0281

AC:

730

AN:

26008

East Asian (EAS)

AF:

0.000305

AC:

AN:

39406

South Asian (SAS)

AF:

0.0181

AC:

1536

AN:

85028

European-Finnish (FIN)

AF:

0.0239

AC:

1266

AN:

52926

Middle Eastern (MID)

AF:

0.0574

AC:

331

AN:

5766

European-Non Finnish (NFE)

AF:

0.0166

AC:

18389

AN:

1109228

Other (OTH)

AF:

0.0198

AC:

1188

AN:

60152

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1536

3072

4607

6143

7679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.0135

AC:

2062

AN:

152262

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1018

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.00291

AC:

121

AN:

41566

American (AMR)

AF:

0.0142

AC:

217

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0360

AC:

125

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5168

South Asian (SAS)

AF:

0.0187

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0224

AC:

238

AN:

10610

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0180

AC:

1224

AN:

68008

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<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:

0.0160

Hom.:

105

Bravo

AF:

0.0125

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0164

AC:

141

ExAC

AF:

0.0162

AC:

1961

Asia WGS

AF:

0.00924

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Hyperprolinemia type 2

Benign:2

Jan 12, 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.

Feb 02, 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

0.60

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.066

T;.;T;.

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.0

.;D;D;D

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

N;N;N;.

PhyloP100

4.4

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.84

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.35

T;T;T;T

Sift4G

Benign

0.44

T;T;T;T

Vest4

0.35

ClinPred

0.013

GERP RS

3.1

Varity_R

0.20

gMVP

0.79

Mutation Taster

=88/12

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