dbSNP rs567406933: KDM3A:p.Gly186Asp (chr2-86456442-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018433.6(KDM3A):c.557G>A(p.Gly186Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G186V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KDM3A
NM_018433.6 missense, splice_region

Scores

Splicing: ADA: 0.9991

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.52

Publications

0 publications found

Variant links:

Genes affected

KDM3A (HGNC:20815): (lysine demethylase 3A) Enables androgen receptor binding activity; histone H3-methyl-lysine-9 demethylase activity; and iron ion binding activity. Involved in several processes, including androgen receptor signaling pathway; formaldehyde biosynthetic process; and histone H3-K9 demethylation. Located in nucleoplasm. Implicated in cervical cancer and colon cancer. Biomarker of Ewing sarcoma; hepatocellular carcinoma; nasopharynx carcinoma; and prostate cancer. [provided by Alliance of Genome Resources, Apr 2022]

KDM3A links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018433.6. 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
	KDM3A	NM_018433.6	MANE Select	c.557G>A	p.Gly186Asp	missense splice_region	Exon 6 of 26	NP_060903.2
	KDM3A	NM_001146688.2		c.557G>A	p.Gly186Asp	missense splice_region	Exon 6 of 26	NP_001140160.1	Q9Y4C1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDM3A	ENST00000312912.10	TSL:1 MANE Select	c.557G>A	p.Gly186Asp	missense splice_region	Exon 6 of 26	ENSP00000323659.5	Q9Y4C1
KDM3A	ENST00000409064.5	TSL:1	c.557G>A	p.Gly186Asp	missense splice_region	Exon 6 of 26	ENSP00000386516.1	Q9Y4C1
KDM3A	ENST00000900202.1		c.557G>A	p.Gly186Asp	missense splice_region	Exon 6 of 26	ENSP00000570261.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1257172

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

625644

African (AFR)

AF:

0.00

AC:

AN:

25354

American (AMR)

AF:

0.00

AC:

AN:

22668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21346

East Asian (EAS)

AF:

0.00

AC:

AN:

33432

South Asian (SAS)

AF:

0.00

AC:

AN:

66270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

984642

Other (OTH)

AF:

0.00

AC:

AN:

51308

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.81

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.1

REVEL

Benign

0.16

Sift

Uncertain

0.0010

Sift4G

Benign

0.081

Polyphen

0.93

Vest4

0.82

MutPred

0.29

Gain of relative solvent accessibility (P = 0.0507)

MVP

0.23

MPC

0.58

ClinPred

0.98

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.68

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.90

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over