12-49022063-G-A

Position:

• chr12-49022063-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.16501C>T​(p.Arg5501Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 1.41

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-49022063-G-A is Pathogenic according to our data. Variant chr12-49022063-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 280126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49022063-G-A is described in Lovd as [Pathogenic]. Variant chr12-49022063-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.16501C>T	p.Arg5501Ter	stop_gained	54/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.16501C>T	p.Arg5501Ter	stop_gained	54/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Autoinflammatory diseases unit, CHU de Montpellier	Apr 30, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is not observed in the gnomAD v2.1.1 dataset. This stop-gained (nonsense) variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been observed in at least two similarly affected unrelated individuals (PMID: 27302555). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least two similarly affected unrelated individuals (PMID: 27302555, 28884922). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000280126/PMID: 20711175). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Jul 12, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2019	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20711175, 25525159, 27302555, 28884922, 29568095) -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 06, 2023	- -

Kabuki syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 04, 2022

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 280126). This premature translational stop signal has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 2071175, 28884922). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg5501*) in the KMT2D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the KMT2D protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	49
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	D
Vest4		0.75
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs886041398; hg19: chr12-49415846; COSMIC: COSV56407191; COSMIC: COSV56407191;