X-44873571-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_001291415.2(KDM6A):c.20C>G(p.Ser7Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000366 in 1,093,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000037 (0 hom. 2 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2	c.20C>G	p.Ser7Trp	missense_variant	1/30	ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5	c.20C>G	p.Ser7Trp	missense_variant	1/30	1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1093220 Hom.: 0 Cov.: 32 AF XY: 0.00000555 AC XY: 2 AN XY: 360264

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: 0.00000476

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.0000113

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2023

The c.20C>G (p.S7W) alteration is located in exon 1 (coding exon 1) of the KDM6A gene. This alteration results from a C to G substitution at nucleotide position 20, causing the serine (S) at amino acid position 7 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 22, 2020

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.4	D;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.67
MutPred		0.44		Loss of glycosylation at S7 (P = 0.0168);Loss of glycosylation at S7 (P = 0.0168);
MVP		0.95
MPC		2.2
ClinPred		0.95	D
GERP RS		4.4
Varity_R		0.87
gMVP		0.90

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: rs770931883; hg19: chrX-44732817; COSMIC: COSV100937998; COSMIC: COSV100937998;