16-27210221-T-A

Position:

• chr16-27210221-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000286096.9(KDM8):​c.98T>A​(p.Leu33Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KDM8 ENST00000286096.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05

Genes affected

KDM8 (HGNC:25840): (lysine demethylase 8) This gene likely encodes a histone lysine demethylase. Studies of a similar protein in mouse indicate a potential role for this protein as a tumor suppressor. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36489278).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDM8	NM_024773.3	c.98T>A	p.Leu33Gln	missense_variant	2/8	ENST00000286096.9	NP_079049.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDM8	ENST00000286096.9	c.98T>A	p.Leu33Gln	missense_variant	2/8	1	NM_024773.3	ENSP00000286096	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 13, 2023

The c.212T>A (p.L71Q) alteration is located in exon 2 (coding exon 2) of the KDM8 gene. This alteration results from a T to A substitution at nucleotide position 212, causing the leucine (L) at amino acid position 71 to be replaced by a glutamine (Q). 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	0.21
BayesDel_addAF	Benign	0.0032	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.36	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;M
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;D;D;D;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		1.0	D;.;D;.;D
Vest4		0.71
MutPred		0.33		Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);.;Loss of stability (P = 0.0232);Loss of stability (P = 0.0232);
MVP		0.64
MPC		0.71
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.32
gMVP		0.59

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: rs2083467855; hg19: chr16-27221542;