rs1452715535

Positions:

• chr12-49041475-G-A
• chr12-49041475-G-C
• chr12-49041475-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.6295C>T​(p.Arg2099Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 5.46

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49041475-G-A is Pathogenic according to our data. Variant chr12-49041475-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 521015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49041475-G-A is described in Lovd as [Pathogenic]. Variant chr12-49041475-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.6295C>T	p.Arg2099Ter	stop_gained	32/55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.6295C>T	p.Arg2099Ter	stop_gained	32/55	5	NM_003482.4	ENSP00000301067	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 04, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Feb 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2018	The R2099X variant in the KMT2D gene has been reported in association with Kabuki syndrome (Ng et al., 2010; Micale et al., 2011; Banka et al., 2012; Bögershausen et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R2099X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R2099X as a pathogenic variant. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2016

- -

Intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Apr 20, 2020

- -

KMT2D-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2024

The KMT2D c.6295C>T variant is predicted to result in premature protein termination (p.Arg2099*). This variant has been reported in individuals with Kabuki syndrome (see for example, Cocciadiferro et al. 2018. PubMed ID: 30107592; reported as de novo in Mellis et al. 2022. PubMed ID: 34411415; Murakami et al. 2020. PubMed ID: 32803813). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in KMT2D are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A
Vest4		0.85
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: -33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1452715535; hg19: chr12-49435258; COSMIC: COSV56487468; COSMIC: COSV56487468;