1-18875462-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003748.4(ALDH4A1):​c.1380T>A​(p.Asp460Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. D460G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ALDH4A1
NM_003748.4 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.089517534).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALDH4A1NM_003748.4 linkuse as main transcriptc.1380T>A p.Asp460Glu missense_variant 13/15 ENST00000375341.8
ALDH4A1NM_170726.3 linkuse as main transcriptc.1380T>A p.Asp460Glu missense_variant 13/16
ALDH4A1NM_001319218.2 linkuse as main transcriptc.1227T>A p.Asp409Glu missense_variant 12/14
ALDH4A1NM_001161504.2 linkuse as main transcriptc.1200T>A p.Asp400Glu missense_variant 13/15

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH4A1ENST00000375341.8 linkuse as main transcriptc.1380T>A p.Asp460Glu missense_variant 13/151 NM_003748.4 P1P30038-1
ALDH4A1ENST00000290597.9 linkuse as main transcriptc.1380T>A p.Asp460Glu missense_variant 13/161 P1P30038-1
ALDH4A1ENST00000538839.5 linkuse as main transcriptc.1227T>A p.Asp409Glu missense_variant 12/141 P30038-3
ALDH4A1ENST00000538309.5 linkuse as main transcriptc.1200T>A p.Asp400Glu missense_variant 13/152 P30038-2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
67
AF XY:
0.00000138
AC XY:
1
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.21
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.74
CADD
Benign
0.0030
DANN
Benign
0.91
DEOGEN2
Uncertain
0.43
T;.;T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-2.0
FATHMM_MKL
Benign
0.010
N
LIST_S2
Uncertain
0.88
.;D;T;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.090
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.70
N;.;N;.
MutationTaster
Benign
0.96
P;P;P;P
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-2.6
D;N;D;D
REVEL
Benign
0.085
Sift
Benign
0.19
T;T;T;T
Sift4G
Benign
0.26
T;T;T;T
Polyphen
0.10
B;.;B;.
Vest4
0.12
MutPred
0.56
Loss of ubiquitination at K464 (P = 0.1062);.;Loss of ubiquitination at K464 (P = 0.1062);.;
MVP
0.14
MPC
0.14
ClinPred
0.50
D
GERP RS
-10
Varity_R
0.33
gMVP
0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2230708; hg19: chr1-19201956; API