chr12-49043918-G-A

Variant names:

• chr12-49043918-G-A
• rs1555194045
• NM_003482.4:c.5269C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.5269C>T​(p.Arg1757*) 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 (★★). 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:5
• Conservation: PhyloP100: 2.17
• Publications: 4 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 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 12-49043918-G-A is Pathogenic according to our data. Variant chr12-49043918-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 435669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.5269C>T	p.Arg1757*	stop_gained	Exon 23 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.5269C>T	p.Arg1757*	stop_gained	Exon 23 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome 1 Pathogenic:2

Sep 28, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Jan 02, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 23, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28991257, 26411453, 22434255, 25142838, 30107592, 32170002, 32368696, 33767182, 33084842, 36625521, 31941532, 34539730, 23913813, 37908464) -

KMT2D-related disorder Pathogenic:1

Aug 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KMT2D c.5269C>T variant is predicted to result in premature protein termination (p.Arg1757*). This variant was reported de novo in multiple individuals with Kabuki syndrome (See for example, Table 1, Miyake et al. 2013. PubMed ID: 23913813; Table 2, Lin et al. 2014. PubMed ID: 25142838; Table 4, Martinez-Granero et al. 2021. PubMed ID: 33767182). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), 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	0.44
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Benign	0.69	D
PhyloP100		2.2
Vest4		0.90
GERP RS		4.0
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1555194045; hg19: chr12-49437701; COSMIC: COSV56464914;