9-6849689-G-T

Variant names:

• chr9-6849689-G-T
• rs7864351
• NM_015061.6:c.618G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015061.6(KDM4C):​c.618G>T​(p.Glu206Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,561,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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 the same amino acid substitution has been previously reported as Benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KDM4C NM_015061.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 6 publications found

Genes affected

KDM4C (HGNC:17071): (lysine demethylase 4C) This gene is a member of the Jumonji domain 2 (JMJD2) family. The encoded protein is a trimethylation-specific demethylase, and converts specific trimethylated histone residues to the dimethylated form. This enzymatic action regulates gene expression and chromosome segregation. Chromosomal aberrations and changes in expression of this gene may be found in tumor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37990734).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015061.6. 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
	KDM4C	NM_015061.6	MANE Select	c.618G>T	p.Glu206Asp	missense	Exon 5 of 22	NP_055876.2	Q9H3R0-1
	KDM4C	NM_001353997.3		c.618G>T	p.Glu206Asp	missense	Exon 5 of 23	NP_001340926.1
	KDM4C	NM_001304339.4		c.618G>T	p.Glu206Asp	missense	Exon 5 of 22	NP_001291268.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4C	ENST00000381309.8	TSL:1 MANE Select	c.618G>T	p.Glu206Asp	missense	Exon 5 of 22	ENSP00000370710.3	Q9H3R0-1
	KDM4C	ENST00000536108.7	TSL:1	c.618G>T	p.Glu206Asp	missense	Exon 5 of 18	ENSP00000440656.4	Q9H3R0-3
	KDM4C	ENST00000948679.1		c.618G>T	p.Glu206Asp	missense	Exon 6 of 23	ENSP00000618738.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409112 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693666

African (AFR) AF: 0.00 AC: 0 AN: 32272

American (AMR) AF: 0.00 AC: 0 AN: 41014

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24866

East Asian (EAS) AF: 0.00 AC: 0 AN: 38596

South Asian (SAS) AF: 0.00 AC: 0 AN: 78448

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00000186 AC: 2 AN: 1078166

Other (OTH) AF: 0.00 AC: 0 AN: 57938

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152116 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74296

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.069	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.040	D
Sift4G	Benign	0.15	T
Polyphen		0.65	P
Vest4		0.68
MutPred		0.27		Loss of ubiquitination at K208 (P = 0.1403)
MVP		0.61
MPC		0.21
ClinPred		0.80	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.80
Mutation Taster		=94/6	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: rs7864351; hg19: chr9-6849689;