10-5102114-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Moderate BP6_Moderate

The NM_003739.6(AKR1C3):c.584C>T(p.Pro195Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000386 in 1,611,672 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (2 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07362792).
• BP6: Variant 10-5102114-C-T is Benign according to our data. Variant chr10-5102114-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 716665.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.584C>T	p.Pro195Leu	missense_variant	6/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.584C>T	p.Pro195Leu	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.584C>T	p.Pro195Leu	missense_variant	6/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.584C>T	p.Pro195Leu	missense_variant	6/9	5		A1
AKR1C3	ENST00000605149.5	c.515C>T	p.Pro172Leu	missense_variant	6/9	2
AKR1C3	ENST00000605781.5	n.763C>T		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152034 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000514 AC: 129 AN: 251210 Hom.: 1 AF XY: 0.000633 AC XY: 86 AN XY: 135772

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000677

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000386 AC: 563 AN: 1459520 Hom.: 2 Cov.: 30 AF XY: 0.000410 AC XY: 298 AN XY: 726252

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000353

Gnomad4 OTH exome AF: 0.000829

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152152 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74392

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000691 Hom.: 0

Bravo AF: 0.000480

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000948

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	14
Dann	Benign	0.68
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.074	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.75	D;D
PrimateAI	Benign	0.42	T
REVEL	Benign	0.18
Sift4G	Uncertain	0.054	T;D;T
Polyphen		0.71	.;.;P
Vest4		0.43
MVP		0.51
MPC		0.034
ClinPred		0.093	T
GERP RS		0.070
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.50
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs151229504; hg19: chr10-5144306;