Variant 10-4972309-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_001353.6(AKR1C1):c.679T>C(p.Trp227Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

AKR1C1
NM_001353.6 missense, splice_region

Scores

Splicing: ADA: 0.0005088

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.32

Variant links:

Genes affected

AKR1C1 (HGNC:384): (aldo-keto reductase family 1 member C1) 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 reaction of progesterone to the inactive form 20-alpha-hydroxy-progesterone. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

AKR1C1 links:

LOC124902365 (HGNC:):

LOC124902365 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity AK1C1_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C1	NM_001353.6 link	c.679T>C	p.Trp227Arg	missense_variant, splice_region_variant	6/9	ENST00000380872.9	NP_001344.2	Q04828
LOC124902365	XR_007062038.1 link	n.263+90A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AKR1C1	ENST00000380872.9 link	c.679T>C	p.Trp227Arg	missense_variant, splice_region_variant	6/9	1	NM_001353.6	ENSP00000370254.4	Q04828
AKR1C1	ENST00000442997.5 link	c.577T>C	p.Trp193Arg	missense_variant, splice_region_variant	6/7	3		ENSP00000416415.1	H0Y804
AKR1C1	ENST00000477661.1 link	n.2136T>C		splice_region_variant, non_coding_transcript_exon_variant	5/8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251060

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461586

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

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:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

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

May 24, 2023

The c.679T>C (p.W227R) alteration is located in exon 6 (coding exon 6) of the AKR1C1 gene. This alteration results from a T to C substitution at nucleotide position 679, causing the tryptophan (W) at amino acid position 227 to be replaced by an arginine (R). 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

0.80

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.56

DEOGEN2

Benign

0.15

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.80

M_CAP

Benign

0.0017

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PROVEAN

Pathogenic

-12

REVEL

Benign

0.20

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.021

Polyphen

0.66

Vest4

0.58

MutPred

0.53

Gain of disorder (P = 0.0101);

MVP

0.26

MPC

2.8

ClinPred

0.73

GERP RS

0.54

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.54

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00051

dbscSNV1_RF

Benign

0.062

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over