rs1555188379

Variant names:

• chr12-49032761-G-A
• rs1555188379
• NM_003482.4:c.11944C>T
• KMT2D p.Arg3982*

Your query was ambiguous. Multiple possible variants found:

• chr12-49032761-G-A
• chr12-49032761-G-C
• chr12-49032761-G-T

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO2_Very_StrongO3_ModerateO4_Moderate

The NM_003482.4(KMT2D):c.11944C>T (p.Arg3982*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The gene KMT2D is a tumor suppressor gene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The gene KMT2D is a known oncogene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The gene KMT2D is a cancer driver gene (CancerMine: 29 TSG, 29 oncogene, 10 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). The variant has been observed in cBioPortal in 22 samples across 13 studies and 7 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adenomas and Adenocarcinomas.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.28
• Publications: 2 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, STRONG, MODERATE Submitted by: G2P, Illumina, PanelApp Australia
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Laboratory for Molecular Medicine, ClinGen
• 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O2Null variant in tumour suppressor gene		Frameshift/stop-gained, NMD predicted, LoF oncogenic mechanism — O2 very strong (+8); Use caution in the presence of multiple transcripts; Gene confirmed as TSG in CancerMine (TSG: 29 citations, oncogene: 29 citations, driver: 10 citations).; Frameshift/stop-gained. NMD predicted: true. LoF mechanism: true. Downstream pathogenic count: 0.
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=22 | studies=13 | cancer types=7 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D NM_003482.4	MANE Select	c.11944C>T p.Arg3982*	stop_gained	Exon 40 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.11944C>Tp.Arg3982*

Exon rankExon 40 of 55

stop_gained

Prot: NP_003473.3UniProt: O14686-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KMT2D ENST00000301067.12	TSL:5MANE Select	c.11944C>T p.Arg3982*	stop_gained	Exon 40 of 55	Prot: ENSP00000301067.7 UniProt:
	KMT2D ENST00000683543.2		c.11944C>T p.Arg3982*	stop_gained	Exon 40 of 56	Prot: ENSP00000506726.1 UniProt:
	KMT2D ENST00000685166.1		c.11953C>T p.Arg3985*	stop_gained	Exon 39 of 54	Prot: ENSP00000509386.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.11944C>Tp.Arg3982*

Exon rankExon 40 of 55

stop_gained

Prot: ENSP00000301067.7UniProt: O14686-1

KMT2D ENST00000683543.2

HGVSc / HGVSpc.11944C>Tp.Arg3982*

Exon rankExon 40 of 56

stop_gained

Prot: ENSP00000506726.1UniProt: A0A804HHR9

KMT2D ENST00000685166.1

HGVSc / HGVSpc.11953C>Tp.Arg3985*

Exon rankExon 39 of 54

stop_gained

Prot: ENSP00000509386.1UniProt: O14686-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:47
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)
1	-	-	Kabuki syndrome (1)
1	-	-	Kabuki syndrome 1 (1)
1	-	-	not provided (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	37
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.89	D
GPN-Star LLR	N/A	-5.5
GPN-Star score	N/A	5.5
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Benign	2.3

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1555188379;

hg19: chr12-49426544;

COSMIC: COSV56450787;

COSMIC: COSV56450787;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar