chr11-94998430-C-T

Variant names:

• chr11-94998430-C-T
• rs782340199
• NM_018039.3:c.1058C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018039.3(KDM4D):​c.1058C>T​(p.Pro353Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: KDM4D NM_018039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.14
• Publications: 0 publications found

Genes affected

KDM4D (HGNC:25498): (lysine demethylase 4D) Enables histone H3-methyl-lysine-9 demethylase activity. Involved in histone H3-K9 demethylation. Acts upstream of or within several processes, including cellular response to ionizing radiation; positive regulation of chromatin binding activity; and positive regulation of double-strand break repair via nonhomologous end joining. Located in site of double-strand break. Biomarker of nephroblastoma. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000299693 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069503695).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018039.3. 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
	KDM4D	NM_018039.3	MANE Select	c.1058C>T	p.Pro353Leu	missense	Exon 3 of 3	NP_060509.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDM4D	ENST00000335080.6	TSL:1 MANE Select	c.1058C>T	p.Pro353Leu	missense	Exon 3 of 3	ENSP00000334181.5	Q6B0I6
	KDM4D	ENST00000536741.1	TSL:4	c.1058C>T	p.Pro353Leu	missense	Exon 2 of 2	ENSP00000460897.1	Q6B0I6
	KDM4D	ENST00000610872.1	TSL:6	c.1058C>T	p.Pro353Leu	missense	Exon 1 of 1	ENSP00000482224.1	Q6B0I6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152188 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

GnomAD2 exomes AF: 0.0000319 AC: 8 AN: 250876 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

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 AF: 0.00000479 AC: 7 AN: 1461498 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727054

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152188 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

⚠️ 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: 41452

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ 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: 0.0000113

ExAC AF: 0.0000330 AC: 4

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	Benign	0.063
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.021
DANN	Benign	0.45
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-2.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.0080
Sift	Benign	0.34	T
Sift4G	Benign	0.43	T
Polyphen		0.54	P
Vest4		0.072
MutPred		0.35		Loss of disorder (P = 0.0349)
MVP		0.13
MPC		0.60
ClinPred		0.055	T
GERP RS		-0.50
Varity_R		0.029
gMVP		0.31
Mutation Taster		=98/2	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: rs782340199; hg19: chr11-94731594;