rs34922269

chrX-45063635-A-GchrX-45063635-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001291415.2(KDM6A):c.1897A>G(p.Thr633Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,208,652 control chromosomes in the GnomAD database, including 9 homozygotes. There are 363 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (5 hom., 166 hem., cov: 22)
  • Exomes 𝑓: 0.00066 (4 hom. 197 hem.)
• Consequence: KDM6A NM_001291415.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.71

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007016927).
• BP6: Variant X-45063635-A-G is Benign according to our data. Variant chrX-45063635-A-G is described in ClinVar as [Benign]. Clinvar id is 261405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-45063635-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00585 (653/111626) while in subpopulation AFR AF= 0.02 (615/30687). AF 95% confidence interval is 0.0187. There are 5 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDM6A	NM_001291415.2	c.1897A>G	p.Thr633Ala	missense_variant	17/30	ENST00000611820.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDM6A	ENST00000611820.5	c.1897A>G	p.Thr633Ala	missense_variant	17/30	1	NM_001291415.2	P4

Frequencies

GnomAD3 genomes AF: 0.00583 AC: 650 AN: 111574 Hom.: 5 Cov.: 22 AF XY: 0.00489 AC XY: 165 AN XY: 33758

Gnomad AFR AF: 0.0200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00247

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000151

Gnomad OTH AF: 0.00266

GnomAD3 exomes AF: 0.00175 AC: 317 AN: 181660 Hom.: 2 AF XY: 0.00110 AC XY: 73 AN XY: 66246

Gnomad AFR exome AF: 0.0213

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000530

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000989

Gnomad OTH exome AF: 0.000223

GnomAD4 exome AF: 0.000657 AC: 721 AN: 1097026 Hom.: 4 Cov.: 30 AF XY: 0.000544 AC XY: 197 AN XY: 362408

Gnomad4 AFR exome AF: 0.0213

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000740

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000499

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00585 AC: 653 AN: 111626 Hom.: 5 Cov.: 22 AF XY: 0.00491 AC XY: 166 AN XY: 33820

Gnomad4 AFR AF: 0.0200

Gnomad4 AMR AF: 0.00247

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000151

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.00107 Hom.: 32

Bravo AF: 0.00677

ESP6500AA AF: 0.0167 AC: 64

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00193 AC: 234

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2018	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 25, 2020

- -

Kabuki syndrome 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
Cadd	Uncertain	23
Dann	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0070	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.51	T
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.82	.;.;.;.;P
Vest4		0.46
MVP		0.48
MPC		0.11
ClinPred		0.052	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34922269; hg19: chrX-44922880;