11-94997556-A-T

Variant names:

• chr11-94997556-A-T
• NM_018039.3:c.184A>T

Variant summary

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

The NM_018039.3(KDM4D):​c.184A>T​(p.Thr62Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDM4D NM_018039.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190

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]

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=0.049825817).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4D	NM_018039.3	c.184A>T	p.Thr62Ser	missense_variant	Exon 3 of 3	ENST00000335080.6	NP_060509.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM4D	ENST00000335080.6	c.184A>T	p.Thr62Ser	missense_variant	Exon 3 of 3	1	NM_018039.3	ENSP00000334181.5
KDM4D	ENST00000536741.1	c.184A>T	p.Thr62Ser	missense_variant	Exon 2 of 2	4		ENSP00000460897.1
KDM4D	ENST00000610872.1	c.184A>T	p.Thr62Ser	missense_variant	Exon 1 of 1	6		ENSP00000482224.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.184A>T (p.T62S) alteration is located in exon 3 (coding exon 1) of the KDM4D gene. This alteration results from a A to T substitution at nucleotide position 184, causing the threonine (T) at amino acid position 62 to be replaced by a serine (S). 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	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	12
DANN	Benign	0.18
DEOGEN2	Benign	0.042	T;T;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.67	.;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.5	N;.;.
REVEL	Benign	0.057
Sift	Benign	1.0	T;.;.
Sift4G	Benign	0.93	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.068
MutPred		0.34		Gain of disorder (P = 0.0346);Gain of disorder (P = 0.0346);Gain of disorder (P = 0.0346);
MVP		0.17
MPC		0.52
ClinPred		0.017	T
GERP RS		2.6
Varity_R		0.23
gMVP		0.32

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: chr11-94730720;