12-49031255-G-A

Variant names:

• chr12-49031255-G-A
• rs587783690
• NM_003482.4:c.13450C>T
• KMT2D p.Arg4484*

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 (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_003482.4(KMT2D):c.13450C>T (p.Arg4484*) 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 variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0000009, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. 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 (★★). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adenomas and Adenocarcinomas.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 5.67
• Publications: 3 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 40 of 55) at amino acid 4484 of 5537, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000009 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.13450C>T p.Arg4484*	stop_gained	Exon 40 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.13450C>Tp.Arg4484*

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.13450C>T p.Arg4484*	stop_gained	Exon 40 of 55	Prot: ENSP00000301067.7 UniProt:
	KMT2D ENST00000683543.2		c.13450C>T p.Arg4484*	stop_gained	Exon 40 of 56	Prot: ENSP00000506726.1 UniProt:
	KMT2D ENST00000685166.1		c.13459C>T p.Arg4487*	stop_gained	Exon 39 of 54	Prot: ENSP00000509386.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.13450C>Tp.Arg4484*

Exon rankExon 40 of 55

stop_gained

Prot: ENSP00000301067.7UniProt: O14686-1

KMT2D ENST00000683543.2

HGVSc / HGVSpc.13450C>Tp.Arg4484*

Exon rankExon 40 of 56

stop_gained

Prot: ENSP00000506726.1UniProt: A0A804HHR9

KMT2D ENST00000685166.1

HGVSc / HGVSpc.13459C>Tp.Arg4487*

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000402	AC:1	Hom:	AN:248614	Cov:
GnomAD4 exome Warning	AF: 6.85e-7	AC:1	Hom:0	AN:1460742	Cov:39
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:187130	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Kabuki syndrome 1 (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Kabuki syndrome (1)
-	-	-	Neoplasm (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	39
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	10
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	5.7
PromoterAI	N/A	-0.0099	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 15 of 15 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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: rs587783690;

hg19: chr12-49425038;

COSMIC: COSV56434635;

COSMIC: COSV56434635;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar