chr10-5102616-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_003739.6(AKR1C3):c.812G>A(p.Ser271Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000591 in 1,354,350 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: 28)
Exomes 𝑓: 0.0000059 ( 0 hom. )
Consequence
AKR1C3
NM_003739.6 missense
NM_003739.6 missense
Scores
3
7
5
Clinical Significance
Conservation
PhyloP100: 4.93
Genes affected
AKR1C3 (HGNC:386): (aldo-keto reductase family 1 member C3) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the reduction of prostaglandin (PG) D2, PGH2 and phenanthrenequinone (PQ), and the oxidation of 9alpha,11beta-PGF2 to PGD2. It may play an important role in the pathogenesis of allergic diseases such as asthma, and may also have a role in controlling cell growth and/or differentiation. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]
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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, 0.948
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AKR1C3 | NM_003739.6 | c.812G>A | p.Ser271Asn | missense_variant | 7/9 | ENST00000380554.5 | |
AKR1C3 | NM_001253908.2 | c.812G>A | p.Ser271Asn | missense_variant | 7/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AKR1C3 | ENST00000380554.5 | c.812G>A | p.Ser271Asn | missense_variant | 7/9 | 1 | NM_003739.6 | P4 | |
AKR1C3 | ENST00000439082.7 | c.812G>A | p.Ser271Asn | missense_variant | 7/9 | 5 | A1 | ||
AKR1C3 | ENST00000605149.5 | c.743G>A | p.Ser248Asn | missense_variant | 7/9 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 28
GnomAD3 genomes
?
Cov.:
28
GnomAD3 exomes AF: 0.0000301 AC: 4AN: 133110Hom.: 0 AF XY: 0.0000434 AC XY: 3AN XY: 69080
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GnomAD4 exome AF: 0.00000591 AC: 8AN: 1354350Hom.: 0 Cov.: 33 AF XY: 0.00000906 AC XY: 6AN XY: 661948
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GnomAD4 genome ? Cov.: 28
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?
Cov.:
28
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?
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4
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 submitter | clinical testing | Ambry Genetics | Sep 22, 2023 | The c.812G>A (p.S271N) alteration is located in exon 7 (coding exon 7) of the AKR1C3 gene. This alteration results from a G to A substitution at nucleotide position 812, causing the serine (S) at amino acid position 271 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
REVEL
Uncertain
Sift4G
Pathogenic
D;D;D
Polyphen
0.99
.;.;D
Vest4
MutPred
Loss of MoRF binding (P = 0.1357);.;Loss of MoRF binding (P = 0.1357);
MVP
MPC
0.080
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at