chr12-49031831-G-C

Variant names:

• chr12-49031831-G-C
• rs1555187827
• NM_003482.4:c.12874C>G
• KMT2D p.Pro4292Ala

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_003482.4(KMT2D):c.12874C>G (p.Pro4292Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000711, 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. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P4292L: Uncertain_significance (ClinVar VariationId 4801191, 1 star); p.P4292= (synonymous): Likely_benign (ClinVar VariationId 2850648, 1 star)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000711 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.

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.12874C>G p.Pro4292Ala	missense	Exon 40 of 55	Prot: NP_003473.3 UniProt:

KMT2D NM_003482.4

MANE Select

HGVSc / HGVSpc.12874C>Gp.Pro4292Ala

Exon rankExon 40 of 55

missense

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.12874C>G p.Pro4292Ala	missense	Exon 40 of 55	Prot: ENSP00000301067.7 UniProt:
	KMT2D ENST00000683543.2		c.12874C>G p.Pro4292Ala	missense	Exon 40 of 56	Prot: ENSP00000506726.1 UniProt:
	KMT2D ENST00000685166.1		c.12883C>G p.Pro4295Ala	missense	Exon 39 of 54	Prot: ENSP00000509386.1 UniProt:

KMT2D ENST00000301067.12

TSL:5MANE Select

HGVSc / HGVSpc.12874C>Gp.Pro4292Ala

Exon rankExon 40 of 55

missense

Prot: ENSP00000301067.7UniProt: O14686-1

KMT2D ENST00000683543.2

HGVSc / HGVSpc.12874C>Gp.Pro4292Ala

Exon rankExon 40 of 56

missense

Prot: ENSP00000506726.1UniProt: A0A804HHR9

KMT2D ENST00000685166.1

HGVSc / HGVSpc.12883C>Gp.Pro4295Ala

Exon rankExon 39 of 54

missense

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 Warning	AF: 7.11e-7	AC:1	Hom:0	AN:1406792	Cov:39
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.063
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.056	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.85	D
FuncVEP CTI	Benign	0.021
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.11	D
Mutation Taster	N/A	42/58	disease causing
MutationAssessor	Benign	0.0	N
PhyloP100	Uncertain	4.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.6	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Varity_R	N/A	0.25
VESM-3B	Benign	-2.6

Showing 28 of 28 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: rs1555187827;

hg19: chr12-49425614;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar