Genetic Variant NM_003748.4:c.413C>G (chr1-18885513-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003748.4(ALDH4A1):c.413C>G(p.Pro138Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000287 in 1,395,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P138L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26330987).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ALDH4A1	NM_003748.4 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 5 of 15	ENST00000375341.8	NP_003739.2
ALDH4A1	NM_170726.3 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 5 of 16		NP_733844.1
ALDH4A1	NM_001319218.2 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 5 of 14		NP_001306147.1
ALDH4A1	NM_001161504.2 link	c.233C>G	p.Pro78Arg	missense_variant	Exon 5 of 15		NP_001154976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH4A1	ENST00000375341.8 link	c.413C>G	p.Pro138Arg	missense_variant	Exon 5 of 15	1	NM_003748.4	ENSP00000364490.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000894

AC:

AN:

223664

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000201

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1395438

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

692416

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

41002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23902

East Asian (EAS)

AF:

0.00

AC:

AN:

35018

South Asian (SAS)

AF:

0.00

AC:

AN:

83380

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5460

European-Non Finnish (NFE)

AF:

0.00000373

AC:

AN:

1070966

Other (OTH)

AF:

0.00

AC:

AN:

56174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.070

T;.;T;.;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.26

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.81

.;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.26

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L;L;.;.

PhyloP100

6.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.37

N;N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.073

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;.

Polyphen

0.39

B;.;B;.;.

Vest4

0.59

MutPred

0.51

Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);Gain of MoRF binding (P = 0.0031);.;.;

MVP

0.40

MPC

0.13

ClinPred

0.17

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.12

gMVP

0.52

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over