9-6984275-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015061.6(KDM4C):c.1225G>A(p.Asp409Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KDM4C NM_015061.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.817

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06606674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM4C	NM_015061.6	c.1225G>A	p.Asp409Asn	missense_variant	10/22	ENST00000381309.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM4C	ENST00000381309.8	c.1225G>A	p.Asp409Asn	missense_variant	10/22	1	NM_015061.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.1225G>A (p.D409N) alteration is located in exon 10 (coding exon 9) of the KDM4C gene. This alteration results from a G to A substitution at nucleotide position 1225, causing the aspartic acid (D) at amino acid position 409 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	10
Dann	Uncertain	0.98
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.66	T;T;T;T;T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.066	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
REVEL	Benign	0.081
Polyphen		0.12, 0.012	.;B;B;.;.
Vest4		0.084, 0.066, 0.080, 0.067
MutPred		0.17		.;Gain of MoRF binding (P = 0.0744);Gain of MoRF binding (P = 0.0744);Gain of MoRF binding (P = 0.0744);.;
MVP		0.14
MPC		0.044
ClinPred		0.31	T
GERP RS		0.089
Varity_R		0.028
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-6984275;