NM_018433.6:c.557G>T

Variant names:

• chr2-86456442-G-T
• rs567406933
• NM_018433.6:c.557G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_018433.6(KDM3A):​c.557G>T​(p.Gly186Val) variant causes a missense, splice region change. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G186G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000021 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KDM3A NM_018433.6 missense, splice_region
• Scores: Splicing: ADA: 0.9988
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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>T	p.Gly186Val	missense splice_region	Exon 6 of 26	NP_060903.2
	KDM3A	NM_001146688.2		c.557G>T	p.Gly186Val	missense splice_region	Exon 6 of 26	NP_001140160.1	Q9Y4C1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM3A	ENST00000312912.10	TSL:1 MANE Select	c.557G>T	p.Gly186Val	missense splice_region	Exon 6 of 26	ENSP00000323659.5	Q9Y4C1
	KDM3A	ENST00000409064.5	TSL:1	c.557G>T	p.Gly186Val	missense splice_region	Exon 6 of 26	ENSP00000386516.1	Q9Y4C1
	KDM3A	ENST00000900202.1		c.557G>T	p.Gly186Val	missense splice_region	Exon 6 of 26	ENSP00000570261.1

Frequencies

GnomAD3 genomes AF: 0.0000211 AC: 3 AN: 141920 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000219

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000677 AC: 1 AN: 147714 AF XY: 0.0000121

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000406 AC: 51 AN: 1256594 Hom.: 0 Cov.: 24 AF XY: 0.0000480 AC XY: 30 AN XY: 625368

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000118 AC: 3 AN: 25330

American (AMR) AF: 0.0000441 AC: 1 AN: 22664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21344

East Asian (EAS) AF: 0.0000598 AC: 2 AN: 33422

South Asian (SAS) AF: 0.00 AC: 0 AN: 66260

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48396

Middle Eastern (MID) AF: 0.000267 AC: 1 AN: 3750

European-Non Finnish (NFE) AF: 0.0000427 AC: 42 AN: 984142

Other (OTH) AF: 0.0000195 AC: 1 AN: 51286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000211 AC: 3 AN: 142016 Hom.: 0 Cov.: 26 AF XY: 0.0000438 AC XY: 3 AN XY: 68564

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000263 AC: 1 AN: 38066

American (AMR) AF: 0.00 AC: 0 AN: 14154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4924

South Asian (SAS) AF: 0.000220 AC: 1 AN: 4544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000152 AC: 1 AN: 65820

Other (OTH) AF: 0.00 AC: 0 AN: 1960

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.93	P
Vest4		0.77
MutPred		0.34		Loss of disorder (P = 0.0319)
MVP		0.27
MPC		0.58
ClinPred		0.83	D
GERP RS		5.3
Varity_R		0.10
gMVP		0.62
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Other links and lift over

dbSNP: rs567406933; hg19: chr2-86683565;