1-43660364-C-A

Variant names:

• chr1-43660364-C-A
• rs762616511
• NM_014663.3:c.381C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014663.3(KDM4A):​c.381C>A​(p.Phe127Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: KDM4A NM_014663.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.125

Genes affected

KDM4A (HGNC:22978): (lysine demethylase 4A) This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

ENSG00000284989 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM4A	NM_014663.3	c.381C>A	p.Phe127Leu	missense_variant	Exon 4 of 22	ENST00000372396.4	NP_055478.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM4A	ENST00000372396.4	c.381C>A	p.Phe127Leu	missense_variant	Exon 4 of 22	1	NM_014663.3	ENSP00000361473.3
ENSG00000284989	ENST00000645057.1	n.381C>A		non_coding_transcript_exon_variant	Exon 4 of 26			ENSP00000494063.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74340

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.381C>A (p.F127L) alteration is located in exon 4 (coding exon 3) of the KDM4A gene. This alteration results from a C to A substitution at nucleotide position 381, causing the phenylalanine (F) at amino acid position 127 to be replaced by a leucine (L). 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	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.015	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.8	D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.99	D;.
Vest4		0.69
MutPred		0.47		Gain of catalytic residue at F127 (P = 0.0067);Gain of catalytic residue at F127 (P = 0.0067);
MVP		0.47
MPC		1.5
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.92
gMVP		0.79

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: rs762616511; hg19: chr1-44126035;