NM_001291415.2:c.35C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001291415.2(KDM6A):​c.35C>G​(p.Ala12Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,093,291 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A12A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 0.0000027 ( 0 hom. 0 hem. )

Consequence

KDM6A
NM_001291415.2 missense

Scores

2
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.17
Variant links:
Genes affected
KDM6A (HGNC:12637): (lysine demethylase 6A) This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

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ACMG classification

Classification made for transcript

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=0.40055543).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KDM6ANM_001291415.2 linkc.35C>G p.Ala12Gly missense_variant Exon 1 of 30 ENST00000611820.5 NP_001278344.1 A0A087X0R0B7ZKN5Q86TD1B7ZKN6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KDM6AENST00000611820.5 linkc.35C>G p.Ala12Gly missense_variant Exon 1 of 30 1 NM_001291415.2 ENSP00000483595.2 A0A087X0R0

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
0.00000274
AC:
3
AN:
1093291
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
360309
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:
0.00000357
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kabuki syndrome 2 Uncertain:1
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 12 of the KDM6A protein (p.Ala12Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KDM6A-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt KDM6A protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.11
T;.
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.82
D
MetaRNN
Benign
0.40
T;T
MetaSVM
Benign
-0.35
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.79
N;.
REVEL
Benign
0.12
Sift
Uncertain
0.0080
D;.
Sift4G
Uncertain
0.014
D;D
Polyphen
0.043
B;.
Vest4
0.45
MutPred
0.37
Gain of catalytic residue at A11 (P = 0.095);Gain of catalytic residue at A11 (P = 0.095);
MVP
0.60
MPC
0.78
ClinPred
0.68
D
GERP RS
2.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.2
Varity_R
0.31
gMVP
0.73

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: chrX-44732832; COSMIC: COSV65040939; COSMIC: COSV65040939; API