NM_001291415.2:c.4161+14T>C

Variant names:

• chrX-45107550-T-C
• rs5952682
• NM_001291415.2:c.4161+14T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001291415.2(KDM6A):​c.4161+14T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.092 in 1,205,888 control chromosomes in the GnomAD database, including 9,868 homozygotes. There are 35,243 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4281 hom., 6721 hem., cov: 22)
  • Exomes 𝑓: 0.079 (5587 hom. 28522 hem.)
• Consequence: KDM6A NM_001291415.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0720
• Publications: 10 publications found

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]

KDM6A Gene-Disease associations (from GenCC):

• Kabuki syndrome 2

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-45107550-T-C is Benign according to our data. Variant chrX-45107550-T-C is described in ClinVar as Benign. ClinVar VariationId is 158690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDM6A	NM_001291415.2	c.4161+14T>C		intron_variant	Intron 28 of 29	ENST00000611820.5	NP_001278344.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDM6A	ENST00000611820.5	c.4161+14T>C		intron_variant	Intron 28 of 29	1	NM_001291415.2	ENSP00000483595.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 24131 AN: 111264 Hom.: 4270 Cov.: 22

Gnomad AFR AF: 0.603

Gnomad AMI AF: 0.0336

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0661

Gnomad EAS AF: 0.0493

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.0300

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0651

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.106 AC: 19484 AN: 183025 AF XY: 0.0959

Gnomad AFR exome AF: 0.611

Gnomad AMR exome AF: 0.0597

Gnomad ASJ exome AF: 0.0701

Gnomad EAS exome AF: 0.0504

Gnomad FIN exome AF: 0.0331

Gnomad NFE exome AF: 0.0625

Gnomad OTH exome AF: 0.0851

GnomAD4 exome AF: 0.0793 AC: 86791 AN: 1094571 Hom.: 5587 Cov.: 28 AF XY: 0.0791 AC XY: 28522 AN XY: 360617

African (AFR) AF: 0.623 AC: 16387 AN: 26297

American (AMR) AF: 0.0658 AC: 2314 AN: 35158

Ashkenazi Jewish (ASJ) AF: 0.0679 AC: 1313 AN: 19329

East Asian (EAS) AF: 0.0317 AC: 953 AN: 30109

South Asian (SAS) AF: 0.132 AC: 7129 AN: 54024

European-Finnish (FIN) AF: 0.0327 AC: 1322 AN: 40432

Middle Eastern (MID) AF: 0.123 AC: 506 AN: 4123

European-Non Finnish (NFE) AF: 0.0621 AC: 52120 AN: 839143

Other (OTH) AF: 0.103 AC: 4747 AN: 45956

GnomAD4 genome AF: 0.217 AC: 24180 AN: 111317 Hom.: 4281 Cov.: 22 AF XY: 0.200 AC XY: 6721 AN XY: 33583

African (AFR) AF: 0.603 AC: 18309 AN: 30350

American (AMR) AF: 0.111 AC: 1165 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.0661 AC: 175 AN: 2646

East Asian (EAS) AF: 0.0487 AC: 173 AN: 3556

South Asian (SAS) AF: 0.141 AC: 383 AN: 2725

European-Finnish (FIN) AF: 0.0300 AC: 181 AN: 6041

Middle Eastern (MID) AF: 0.140 AC: 30 AN: 215

European-Non Finnish (NFE) AF: 0.0652 AC: 3457 AN: 53057

Other (OTH) AF: 0.186 AC: 284 AN: 1526

Alfa AF: 0.148 Hom.: 1660

Bravo AF: 0.240

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Kabuki syndrome 2 Benign:2

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.5
DANN	Benign	0.64
PhyloP100		-0.072
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5952682; hg19: chrX-44966795; COSMIC: COSV65037578;