10-5097502-A-T

Position:

• chr10-5097502-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003739.6(AKR1C3):​c.321A>T​(p.Gln107His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.254

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1867441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C3	NM_003739.6	c.321A>T	p.Gln107His	missense_variant	3/9	ENST00000380554.5
AKR1C3	NM_001253908.2	c.321A>T	p.Gln107His	missense_variant	3/9
AKR1C3	NM_001253909.2	c.321A>T	p.Gln107His	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C3	ENST00000380554.5	c.321A>T	p.Gln107His	missense_variant	3/9	1	NM_003739.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Oct 26, 2022

The c.321A>T (p.Q107H) alteration is located in exon 3 (coding exon 3) of the AKR1C3 gene. This alteration results from a A to T substitution at nucleotide position 321, causing the glutamine (Q) at amino acid position 107 to be replaced by a histidine (H). 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	Benign	0.30
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	2.8
DANN	Benign	0.73
DEOGEN2	Benign	0.035	T;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.19	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;.;L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.6	.;.;.;D
REVEL	Benign	0.12
Sift	Uncertain	0.019	.;.;.;D
Sift4G	Uncertain	0.037	D;D;D;D
Polyphen		0.14	.;.;.;B
Vest4		0.25, 0.30, 0.25
MutPred		0.43		.;Loss of ubiquitination at K105 (P = 0.0992);.;Loss of ubiquitination at K105 (P = 0.0992);
MVP		0.40
MPC		0.013
ClinPred		0.43	T
GERP RS		-3.6
Varity_R		0.30
gMVP		0.47

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: rs140441894; hg19: chr10-5139694;