1-45561837-C-T

Variant summary

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

The NM_153326.3(AKR1A1):​c.43C>T​(p.Pro15Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,852 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: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AKR1A1
NM_153326.3 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.31
Variant links:
Genes affected
AKR1A1 (HGNC:380): (aldo-keto reductase family 1 member A1) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. This member, also known as aldehyde reductase, is involved in the reduction of biogenic and xenobiotic aldehydes and is present in virtually every tissue. Multiple alternatively spliced transcript variants of this gene exist, all encoding the same protein. [provided by RefSeq, Jan 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, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AKR1A1NM_153326.3 linkc.43C>T p.Pro15Ser missense_variant 2/9 ENST00000351829.9 NP_697021.1 P14550V9HWI0

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AKR1A1ENST00000351829.9 linkc.43C>T p.Pro15Ser missense_variant 2/91 NM_153326.3 ENSP00000312606.4 P14550
AKR1A1ENST00000481885.5 linkc.43C>T p.Pro15Ser missense_variant 2/53 ENSP00000476978.1 V9GYP9

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251456
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461852
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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.:
31

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 GeneticsMar 13, 2023The c.43C>T (p.P15S) alteration is located in exon 3 (coding exon 1) of the AKR1A1 gene. This alteration results from a C to T substitution at nucleotide position 43, causing the proline (P) at amino acid position 15 to be replaced by a serine (S). 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
Pathogenic
0.77
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D;D;.;T;D;T
Eigen
Pathogenic
0.93
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
.;D;D;D;.;D
M_CAP
Benign
0.033
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.7
M;M;.;.;M;.
PrimateAI
Uncertain
0.78
T
PROVEAN
Pathogenic
-7.6
D;.;D;.;D;.
REVEL
Uncertain
0.56
Sift
Pathogenic
0.0
D;.;D;.;D;.
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
1.0
D;D;.;.;D;.
Vest4
0.98
MutPred
0.91
Loss of methylation at K13 (P = 0.1118);Loss of methylation at K13 (P = 0.1118);Loss of methylation at K13 (P = 0.1118);Loss of methylation at K13 (P = 0.1118);Loss of methylation at K13 (P = 0.1118);Loss of methylation at K13 (P = 0.1118);
MVP
0.73
MPC
0.39
ClinPred
1.0
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.95
gMVP
0.96

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

LitVar

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

Other links and lift over

dbSNP: rs1239684840; hg19: chr1-46027509; API