rs913588

chr9-7174673-G-Achr9-7174673-G-T

Variant summary

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

The NM_015061.6(KDM4C):c.3115G>A(p.Val1039Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.474 in 1,613,154 control chromosomes in the GnomAD database, including 187,064 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 0.43 (14438 hom., cov: 32)
  • Exomes 𝑓: 0.48 (172626 hom.)
• Consequence: KDM4C NM_015061.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.15

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001106441).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM4C	NM_015061.6	c.3115G>A	p.Val1039Ile	missense_variant	22/22	ENST00000381309.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM4C	ENST00000381309.8	c.3115G>A	p.Val1039Ile	missense_variant	22/22	1	NM_015061.6	P1
KDM4C	ENST00000428870.6	c.2176G>A	p.Val726Ile	missense_variant	15/15	2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64652 AN: 151896 Hom.: 14444 Cov.: 32

Gnomad AFR AF: 0.343

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.342

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.409

GnomAD3 exomes AF: 0.422 AC: 105845 AN: 251102 Hom.: 23708 AF XY: 0.424 AC XY: 57576 AN XY: 135692

Gnomad AFR exome AF: 0.338

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.164

Gnomad SAS exome AF: 0.360

Gnomad FIN exome AF: 0.526

Gnomad NFE exome AF: 0.497

Gnomad OTH exome AF: 0.441

GnomAD4 exome AF: 0.479 AC: 699664 AN: 1461140 Hom.: 172626 Cov.: 40 AF XY: 0.476 AC XY: 346055 AN XY: 726904

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.351

Gnomad4 ASJ exome AF: 0.379

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.522

Gnomad4 NFE exome AF: 0.511

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.425 AC: 64656 AN: 152014 Hom.: 14438 Cov.: 32 AF XY: 0.424 AC XY: 31507 AN XY: 74294

Gnomad4 AFR AF: 0.342

Gnomad4 AMR AF: 0.376

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.526

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.404

Alfa AF: 0.465 Hom.: 41461

Bravo AF: 0.411

TwinsUK AF: 0.530 AC: 1967

ALSPAC AF: 0.521 AC: 2007

ESP6500AA AF: 0.351 AC: 1546

ESP6500EA AF: 0.498 AC: 4279

ExAC AF: 0.422 AC: 51294

Asia WGS AF: 0.234 AC: 815 AN: 3478

EpiCase AF: 0.483

EpiControl AF: 0.484

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	18
Dann	Benign	0.94
DEOGEN2	Benign	0.0043	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.84	T;T
MetaRNN	Benign	0.0011	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.028
Sift	Benign	0.95	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.011	B;.
Vest4		0.085
MPC		0.058
ClinPred		0.012	T
GERP RS		4.7
Varity_R		0.039
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs913588; hg19: chr9-7174673; COSMIC: COSV67184207; COSMIC: COSV67184207;