chr9-72909651-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000689.5(ALDH1A1):ā€‹c.1309A>Gā€‹(p.Ile437Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,970 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000055 ( 1 hom. )

Consequence

ALDH1A1
NM_000689.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.147
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_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18213779).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALDH1A1NM_000689.5 linkuse as main transcriptc.1309A>G p.Ile437Val missense_variant 11/13 ENST00000297785.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH1A1ENST00000297785.8 linkuse as main transcriptc.1309A>G p.Ile437Val missense_variant 11/131 NM_000689.5 P1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152232
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461738
Hom.:
1
Cov.:
30
AF XY:
0.00000825
AC XY:
6
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.000120
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:
0.0000497
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152232
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

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 GeneticsJul 21, 2021The c.1309A>G (p.I437V) alteration is located in exon 11 (coding exon 11) of the ALDH1A1 gene. This alteration results from a A to G substitution at nucleotide position 1309, causing the isoleucine (I) at amino acid position 437 to be replaced by a valine (V). 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
0.085
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
7.4
DANN
Benign
0.61
DEOGEN2
Benign
0.31
T
Eigen
Benign
-0.96
Eigen_PC
Benign
-0.91
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.3
L
MutationTaster
Benign
0.95
N
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.77
N
REVEL
Benign
0.21
Sift
Benign
0.077
T
Sift4G
Benign
0.21
T
Polyphen
0.0
B
Vest4
0.095
MutPred
0.58
Gain of phosphorylation at T434 (P = 0.1443);
MVP
0.35
MPC
0.36
ClinPred
0.023
T
GERP RS
0.35
Varity_R
0.098
gMVP
0.61

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs756849804; hg19: chr9-75524567; API