rs2030259

Positions:

• chr2-86456519-A-G
• chr2-86456519-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018433.6(KDM3A):​c.634A>G​(p.Ile212Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,606,618 control chromosomes in the GnomAD database, including 467,664 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.80 (48805 hom., cov: 26)
  • Exomes 𝑓: 0.76 (418859 hom.)
• Consequence: KDM3A NM_018433.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.4812926E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM3A	NM_018433.6	c.634A>G	p.Ile212Val	missense_variant	6/26	ENST00000312912.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM3A	ENST00000312912.10	c.634A>G	p.Ile212Val	missense_variant	6/26	1	NM_018433.6	P1

Frequencies

GnomAD3 genomes AF: 0.799 AC: 120608 AN: 150998 Hom.: 48743 Cov.: 26

Gnomad AFR AF: 0.900

Gnomad AMI AF: 0.792

Gnomad AMR AF: 0.736

Gnomad ASJ AF: 0.727

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.784

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.749

GnomAD3 exomes AF: 0.765 AC: 190519 AN: 249086 Hom.: 74029 AF XY: 0.752 AC XY: 101251 AN XY: 134716

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.774

Gnomad ASJ exome AF: 0.728

Gnomad EAS exome AF: 0.956

Gnomad SAS exome AF: 0.581

Gnomad FIN exome AF: 0.788

Gnomad NFE exome AF: 0.760

Gnomad OTH exome AF: 0.756

GnomAD4 exome AF: 0.756 AC: 1099718 AN: 1455508 Hom.: 418859 Cov.: 34 AF XY: 0.749 AC XY: 542754 AN XY: 724298

Gnomad4 AFR exome AF: 0.909

Gnomad4 AMR exome AF: 0.769

Gnomad4 ASJ exome AF: 0.731

Gnomad4 EAS exome AF: 0.956

Gnomad4 SAS exome AF: 0.586

Gnomad4 FIN exome AF: 0.791

Gnomad4 NFE exome AF: 0.755

Gnomad4 OTH exome AF: 0.759

GnomAD4 genome AF: 0.799 AC: 120726 AN: 151110 Hom.: 48805 Cov.: 26 AF XY: 0.794 AC XY: 58595 AN XY: 73758

Gnomad4 AFR AF: 0.900

Gnomad4 AMR AF: 0.736

Gnomad4 ASJ AF: 0.727

Gnomad4 EAS AF: 0.955

Gnomad4 SAS AF: 0.590

Gnomad4 FIN AF: 0.784

Gnomad4 NFE AF: 0.762

Gnomad4 OTH AF: 0.750

Alfa AF: 0.765 Hom.: 112272

Bravo AF: 0.807

TwinsUK AF: 0.749 AC: 2777

ALSPAC AF: 0.754 AC: 2907

ESP6500AA AF: 0.897 AC: 3952

ESP6500EA AF: 0.753 AC: 6476

ExAC AF: 0.766 AC: 92979

Asia WGS AF: 0.784 AC: 2719 AN: 3470

EpiCase AF: 0.752

EpiControl AF: 0.751

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Benign	0.017	T;T;T;T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.22	.;.;T;.
MetaRNN	Benign	5.5e-7	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.97	N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.31	N;.;N;N
REVEL	Benign	0.055
Sift	Benign	0.86	T;.;T;T
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.057
MPC		0.092
ClinPred		0.0024	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.14

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: rs2030259; hg19: chr2-86683642;