12-49026823-C-T

Variant names:

• chr12-49026823-C-T
• rs886041404
• NM_003482.4:c.15143G>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_003482.4(KMT2D):​c.15143G>A​(p.Arg5048His) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5048C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.86
• Publications: 11 publications found

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]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49026824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94180.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 12-49026823-C-T is Pathogenic according to our data. Variant chr12-49026823-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.15143G>A	p.Arg5048His	missense	Exon 49 of 55	NP_003473.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.15143G>A	p.Arg5048His	missense	Exon 49 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.15143G>A	p.Arg5048His	missense	Exon 49 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.15152G>A	p.Arg5051His	missense	Exon 48 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:6

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 08, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 30, 2016

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Wangler Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense KMT2D variant at c.15143G>A (p.R5048H) was discovered on exome through the Texome Project (R01HG011795). This variant has been reported in individuals with Kabuki syndrome 1 (PMID: 3913813, 27302555, 28475860, 29304373, 30459467). This variant has not been observed in gnomAD (PM2) and is predicted to be deleterious by multiple computational models (CADD: 31.000) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.

Nov 28, 2023

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3_strong;PS4_moderate;PM1_moderate;PM2_supporting;PP4_supporting

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc).;Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.;De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.

not provided Pathogenic:2

Dec 15, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patients with Kabuki syndrome in published literature (Miyake et al., 2013; Makrythanasis et al., 2013; Bogershausen et al., 2016); This variant is associated with the following publications: (PMID: 23320472, 23913813, 29304373, 28475860, 30459467, 27302555)

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KMT2D: PS2:Very Strong, PM2, PM5, PS4:Moderate, PP3

Kabuki syndrome Pathogenic:1

Mar 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg5048 amino acid residue in KMT2D. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27302555). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KMT2D protein function. ClinVar contains an entry for this variant (Variation ID: 280132). This missense change has been observed in individual(s) with clinical features of Kabuki syndrome (PMID: 23913813, 27302555, 28475860). 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 replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 5048 of the KMT2D protein (p.Arg5048His).

KMT2D-related disorder Pathogenic:1

Feb 02, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KMT2D c.15143G>A variant is predicted to result in the amino acid substitution p.Arg5048His. This is a recurrent de novo variant that is reported to be causative for Kabuki Syndrome (Miyake et al. 2013. PubMed ID: 23913813; Butcher et al. 2017. PubMed ID: 28475860; Aref-Eshghi et al. 2018. PubMed ID: 29304373). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Furthermore, an alternate nucleotide change affecting the same amino acid (p.Arg5048Cys) has also been reported to be causative for Kabuki Syndrome (Hannibal et al. 2011. PubMed ID: 21671394). In summary, the c.15143G>A (p.Arg5048His) variant is interpreted as pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.43		Gain of loop (P = 0.0312)
MVP		0.85
MPC		1.2
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.0066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.67
gMVP		0.84
Mutation Taster		=12/88	disease causing (ClinVar)

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: rs886041404; hg19: chr12-49420606; COSMIC: COSV56418956; COSMIC: COSV56418956;