10-95611420-T-G

Variant summary

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

The NM_002860.4(ALDH18A1):​c.1946A>C​(p.Lys649Thr) 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 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. K649R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ALDH18A1
NM_002860.4 missense

Scores

1
7
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94
Variant links:
Genes affected
ALDH18A1 (HGNC:9722): (aldehyde dehydrogenase 18 family member A1) This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]

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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=0.25235555).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALDH18A1NM_002860.4 linkc.1946A>C p.Lys649Thr missense_variant Exon 16 of 18 ENST00000371224.7 NP_002851.2 P54886-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALDH18A1ENST00000371224.7 linkc.1946A>C p.Lys649Thr missense_variant Exon 16 of 18 1 NM_002860.4 ENSP00000360268.2 P54886-1
ALDH18A1ENST00000371221.3 linkc.1940A>C p.Lys647Thr missense_variant Exon 16 of 18 1 ENSP00000360265.3 P54886-2
ALDH18A1ENST00000485428.1 linkn.562A>C non_coding_transcript_exon_variant Exon 4 of 4 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461880
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Uncertain
0.024
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.63
D;.
Eigen
Benign
-0.064
Eigen_PC
Benign
0.12
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.25
T;T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.2
L;.
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-3.0
D;D
REVEL
Uncertain
0.32
Sift
Benign
0.056
T;T
Sift4G
Benign
0.098
T;T
Polyphen
0.0030
B;B
Vest4
0.49
MutPred
0.32
Loss of ubiquitination at K649 (P = 0.0244);.;
MVP
0.59
MPC
0.28
ClinPred
0.86
D
GERP RS
5.6
Varity_R
0.20
gMVP
0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-97371177; API