chr10-5102162-T-G

Position:

• chr10-5102162-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003739.6(AKR1C3):​c.632T>G​(p.Ile211Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.632T>G	p.Ile211Ser	missense_variant	6/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.632T>G	p.Ile211Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.632T>G	p.Ile211Ser	missense_variant	6/9	1	NM_003739.6	P4
AKR1C3	ENST00000439082.7	c.632T>G	p.Ile211Ser	missense_variant	6/9	5		A1
AKR1C3	ENST00000605149.5	c.563T>G	p.Ile188Ser	missense_variant	6/9	2
AKR1C3	ENST00000605781.5	n.811T>G		non_coding_transcript_exon_variant	6/6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2023

The c.632T>G (p.I211S) alteration is located in exon 6 (coding exon 6) of the AKR1C3 gene. This alteration results from a T to G substitution at nucleotide position 632, causing the isoleucine (I) at amino acid position 211 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	0.78
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	.;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0038	T
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.81	T
MutationAssessor	Pathogenic	3.6	.;.;H
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.6	.;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0070	.;.;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.94
MutPred		0.82		Gain of disorder (P = 0.0361);.;Gain of disorder (P = 0.0361);
MVP		0.51
MPC		0.082
ClinPred		0.99	D
GERP RS		0.96
Varity_R		0.83
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-5144354;