chr9-72901270-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000689.5(ALDH1A1):​c.1444G>T​(p.Gly482Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ALDH1A1
NM_000689.5 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58
Variant links:
Genes affected
ALDH1A1 (HGNC:402): (aldehyde dehydrogenase 1 family member A1) The protein encoded by this gene belongs to the aldehyde dehydrogenase family. Aldehyde dehydrogenase is the next enzyme after alcohol dehydrogenase in the major pathway of alcohol metabolism. There are two major aldehyde dehydrogenase isozymes in the liver, cytosolic and mitochondrial, which are encoded by distinct genes, and can be distinguished by their electrophoretic mobility, kinetic properties, and subcellular localization. This gene encodes the cytosolic isozyme. Studies in mice show that through its role in retinol metabolism, this gene may also be involved in the regulation of the metabolic responses to high-fat diet. [provided by RefSeq, Mar 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALDH1A1NM_000689.5 linkuse as main transcriptc.1444G>T p.Gly482Cys missense_variant 13/13 ENST00000297785.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH1A1ENST00000297785.8 linkuse as main transcriptc.1444G>T p.Gly482Cys missense_variant 13/131 NM_000689.5 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1455716
Hom.:
0
Cov.:
29
AF XY:
0.00000276
AC XY:
2
AN XY:
724442
show subpopulations
Gnomad4 AFR exome
AF:
0.0000600
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

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 27, 2021The c.1444G>T (p.G482C) alteration is located in exon 13 (coding exon 13) of the ALDH1A1 gene. This alteration results from a G to T substitution at nucleotide position 1444, causing the glycine (G) at amino acid position 482 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.87
D
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.90
D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.94
D
MetaSVM
Benign
-0.53
T
MutationAssessor
Pathogenic
3.7
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.9
D
REVEL
Uncertain
0.53
Sift
Uncertain
0.0070
D
Sift4G
Uncertain
0.045
D
Polyphen
1.0
D
Vest4
0.61
MutPred
0.81
Loss of disorder (P = 0.0078);
MVP
0.48
MPC
1.3
ClinPred
1.0
D
GERP RS
5.6
Varity_R
0.89
gMVP
0.95

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.14
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: chr9-75516186; API