NM_003482.4:c.11547_11557dupACACAGGCTGG

Variant names:

• chr12-49033147-A-ACCAGCCTGTGT
• rs1555188623
• NM_003482.4:c.11547_11557dupACACAGGCTGG

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_SupportingO2_Very_StrongO3_Moderate

The NM_003482.4(KMT2D):c.11547_11557dupACACAGGCTGG (p.Val3853AspfsTer32) variant causes a frameshift change. 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). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.123
• Publications: 0 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 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP (single/no review) — Supporting (O1); O1 contributing sources (1.0 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])

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.11547_11557dupACACAGGCTGG p.Val3853AspfsTer32	frameshift	Exon 40 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.11547_11557dupACACAGGCTGGp.Val3853AspfsTer32

Exon rankExon 40 of 55

frameshift

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.11547_11557dupACACAGGCTGG p.Val3853AspfsTer32	frameshift	Exon 40 of 55	Prot: ENSP00000301067.7 UniProt:
	KMT2D ENST00000683543.2		c.11547_11557dupACACAGGCTGG p.Val3853AspfsTer32	frameshift	Exon 40 of 56	Prot: ENSP00000506726.1 UniProt:
	KMT2D ENST00000685166.1		c.11556_11566dupACACAGGCTGG p.Val3856AspfsTer32	frameshift	Exon 39 of 54	Prot: ENSP00000509386.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.11547_11557dupACACAGGCTGGp.Val3853AspfsTer32

Exon rankExon 40 of 55

frameshift

Prot: ENSP00000301067.7UniProt: O14686-1

KMT2D ENST00000683543.2

HGVSc / HGVSpc.11547_11557dupACACAGGCTGGp.Val3853AspfsTer32

Exon rankExon 40 of 56

frameshift

Prot: ENSP00000506726.1UniProt: A0A804HHR9

KMT2D ENST00000685166.1

HGVSc / HGVSpc.11556_11566dupACACAGGCTGGp.Val3856AspfsTer32

Exon rankExon 39 of 54

frameshift

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, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	1/199	disease causing (ClinVar)
PhyloP100	Benign	0.12

Showing 2 of 2 scores

Splicing Scores

No splicing scores have been computed for this variant.

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: rs1555188623;

hg19: chr12-49426930;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar