11-67181337-A-G

Position:

• chr11-67181337-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012308.3(KDM2A):​c.199A>G​(p.Ile67Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KDM2A NM_012308.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

Genes affected

KDM2A (HGNC:13606): (lysine demethylase 2A) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least six highly degenerated leucine-rich repeats. This family member plays a role in epigenetic silencing. It nucleates at CpG islands and specifically demethylates both mono- and di-methylated lysine-36 of histone H3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

KDM2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2115894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM2A	NM_012308.3	c.199A>G	p.Ile67Val	missense_variant	4/21	ENST00000529006.7	NP_036440.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM2A	ENST00000529006.7	c.199A>G	p.Ile67Val	missense_variant	4/21	1	NM_012308.3	ENSP00000432786.1
KDM2A	ENST00000308783.9	c.148A>G	p.Ile50Val	missense_variant	4/21	1		ENSP00000309302.6
KDM2A	ENST00000398645.6	c.199A>G	p.Ile67Val	missense_variant	4/21	1		ENSP00000381640.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.199A>G (p.I67V) alteration is located in exon 4 (coding exon 3) of the KDM2A gene. This alteration results from a A to G substitution at nucleotide position 199, causing the isoleucine (I) at amino acid position 67 to be replaced by a valine (V). 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	0.15
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.040	.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.52	N;N;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.13	N;N;.
REVEL	Benign	0.076
Sift	Benign	0.64	T;T;.
Sift4G	Benign	0.74	T;T;T
Polyphen		0.21	.;B;.
Vest4		0.34
MutPred		0.42		Loss of catalytic residue at I67 (P = 0.0499);Loss of catalytic residue at I67 (P = 0.0499);.;
MVP		0.59
MPC		1.4
ClinPred		0.49	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.65

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: chr11-66948808;