10-5096426-C-A

Variant names:

• chr10-5096426-C-A
• rs910658045
• NM_003739.6:c.101C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003739.6(AKR1C3):​c.101C>A​(p.Ala34Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A34V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: AKR1C3 NM_003739.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.500
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003739.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C3	NM_003739.6	MANE Select	c.101C>A	p.Ala34Asp	missense	Exon 2 of 9	NP_003730.4
	AKR1C3	NM_001253908.2		c.101C>A	p.Ala34Asp	missense	Exon 2 of 9	NP_001240837.1	A0A0A0MSS8
	AKR1C3	NM_001253909.2		c.101C>A	p.Ala34Asp	missense	Exon 2 of 3	NP_001240838.1	B4DKT3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C3	ENST00000380554.5	TSL:1 MANE Select	c.101C>A	p.Ala34Asp	missense	Exon 2 of 9	ENSP00000369927.3	P42330-1
	AKR1C3	ENST00000480697.6	TSL:1	n.132C>A		non_coding_transcript_exon	Exon 2 of 3
	AKR1C3	ENST00000605322.1	TSL:1	n.128C>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461032 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726822

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86178

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111428

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0030	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.50
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-3.3	D
REVEL	Benign	0.24
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.060	T
Polyphen		0.90	P
Vest4		0.56
MutPred		0.82		Gain of disorder (P = 0.0569)
MVP		0.48
MPC		0.076
ClinPred		0.54	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.68
gMVP		0.78
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs910658045; hg19: chr10-5138618;