NM_001348716.2:c.80C>T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting

The NM_001348716.2(KDM6B):c.80C>T(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000055 ( 0 hom. )

Consequence

KDM6B
NM_001348716.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67

Variant links:

Genes affected

KDM6B (HGNC:29012): (lysine demethylase 6B) The protein encoded by this gene is a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. This protein can also demethylate non-histone proteins such as retinoblastoma protein. Through its demethylation actvity this gene influences cellular differentiation and development, tumorigenesis, inflammatory diseases, and neurodegenerative diseases. This protein has two classical nuclear localization signals at its N-terminus. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

KDM6B links:

LOC124904106 (HGNC:):

LOC124904106 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13564023).

BS2

High AC in GnomAdExome4 at 8 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
KDM6B	NM_001348716.2 link	c.80C>T	p.Ala27Val	missense_variant	Exon 5 of 24	ENST00000448097.7	NP_001335645.1
KDM6B	NM_001080424.2 link	c.80C>T	p.Ala27Val	missense_variant	Exon 4 of 22		NP_001073893.1
LOC124904106	XM_047437265.1 link	c.-106G>A		upstream_gene_variant			XP_047293221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDM6B	ENST00000448097.7 link	c.80C>T	p.Ala27Val	missense_variant	Exon 5 of 24	5	NM_001348716.2	ENSP00000412513.2	O15054-2
KDM6B	ENST00000254846.9 link	c.80C>T	p.Ala27Val	missense_variant	Exon 4 of 22	1		ENSP00000254846.5	O15054-1
KDM6B	ENST00000570632.1 link	c.80C>T	p.Ala27Val	missense_variant	Exon 3 of 9	5		ENSP00000458445.1	I3L0Z0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250638

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000719

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities

Uncertain:1

May 04, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (C>T) at coding nucleotide position 80 of the KDM6B gene which results in an alanine to valine amino acid change at residue 27 in the KDM6B protein. This variant has not been reported in clinical genetics databases or observed in the medical literature in individuals with KDM6B-related disease, to our knowledge. This variant is present in the gnomAD control population dataset (3/250638 alleles or 0.001%). Multiple bioinformatic tools predict that this variant is likely to be damaging, and the Ala27 residue is highly conserved in mammals. Functiol studies assessing the effect of this variant on protein structure or activity have not been performed, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider it to be a variant of uncertain significance. ACMG Criteria: BP1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.046

.;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.35

N;N;.

REVEL

Benign

0.062

Sift

Uncertain

0.0010

D;D;.

Sift4G

Uncertain

0.059

T;T;D

Polyphen

0.29

B;.;.

Vest4

0.58

MutPred

0.35

Loss of glycosylation at S29 (P = 0.1177);Loss of glycosylation at S29 (P = 0.1177);Loss of glycosylation at S29 (P = 0.1177);

MVP

0.18

MPC

0.11

ClinPred

0.34

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.47

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over