9-6981115-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_015061.6(KDM4C):c.1112G>A(p.Arg371Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,610,256 control chromosomes in the GnomAD database, including 15 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (13 hom.)
• Consequence: KDM4C NM_015061.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.196

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003947735).
• BP6: Variant 9-6981115-G-A is Benign according to our data. Variant chr9-6981115-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1803799.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM4C	NM_015061.6	c.1112G>A	p.Arg371Gln	missense_variant	9/22	ENST00000381309.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM4C	ENST00000381309.8	c.1112G>A	p.Arg371Gln	missense_variant	9/22	1	NM_015061.6	P1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152134 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00478

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00231 AC: 571 AN: 246654 Hom.: 2 AF XY: 0.00229 AC XY: 306 AN XY: 133408

Gnomad AFR exome AF: 0.000622

Gnomad AMR exome AF: 0.000299

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000667

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00460

Gnomad OTH exome AF: 0.00184

GnomAD4 exome AF: 0.00324 AC: 4729 AN: 1458004 Hom.: 13 Cov.: 31 AF XY: 0.00304 AC XY: 2206 AN XY: 725230

Gnomad4 AFR exome AF: 0.000602

Gnomad4 AMR exome AF: 0.000546

Gnomad4 ASJ exome AF: 0.0000773

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00401

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152252 Hom.: 2 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74452

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00478

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00360 Hom.: 2

Bravo AF: 0.00264

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00260 AC: 315

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maffucci syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine

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KDM4C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 15, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	6.7
Dann	Benign	0.81
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0039	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
REVEL	Benign	0.051
Polyphen		0.045, 0.011	.;B;B;.;.
Vest4		0.055, 0.051, 0.077
MVP		0.13
MPC		0.044
ClinPred		0.0087	T
GERP RS		-4.8
Varity_R		0.029
gMVP		0.43

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: rs35049841; hg19: chr9-6981115; COSMIC: COSV67185724; COSMIC: COSV67185724;