Genetic Variant KMT2A:p.Glu502Lys (chr11-118472663-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001197104.2(KMT2A):c.1504G>A(p.Glu502Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00583 in 1,612,902 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0058 ( 10 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 89 hom. )

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.45

Publications

14 publications found

Variant links:

Genes affected

KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

KMT2A Gene-Disease associations (from GenCC):

Wiedemann-Steiner syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

KMT2A links:

ENSG00000285827 (HGNC:):

ENSG00000285827 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042158663).

BP6

Variant 11-118472663-G-A is Benign according to our data. Variant chr11-118472663-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00584 (882/151030) while in subpopulation NFE AF = 0.0058 (393/67802). AF 95% confidence interval is 0.00532. There are 10 homozygotes in GnomAd4. There are 511 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 882 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2A	NM_001197104.2	MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 3 of 36	NP_001184033.1
KMT2A	NM_001412597.1		c.1603G>A	p.Glu535Lys	missense	Exon 4 of 37	NP_001399526.1
KMT2A	NM_005933.4		c.1504G>A	p.Glu502Lys	missense	Exon 3 of 36	NP_005924.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.1504G>A	p.Glu502Lys	missense	Exon 3 of 36	ENSP00000436786.2
KMT2A	ENST00000389506.10	TSL:1	c.1504G>A	p.Glu502Lys	missense	Exon 3 of 36	ENSP00000374157.5
ENSG00000285827	ENST00000648261.1		c.274G>A	p.Glu92Lys	missense	Exon 3 of 7	ENSP00000498126.1

Frequencies

GnomAD3 genomes

AF:

0.00584

AC:

882

AN:

150912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000951

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00233

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0388

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00580

Gnomad OTH

AF:

0.00435

GnomAD2 exomes

AF:

0.00663

AC:

1662

AN:

250866

AF XY:

0.00637

show subpopulations

Gnomad AFR exome

AF:

0.000864

Gnomad AMR exome

AF:

0.00182

Gnomad ASJ exome

AF:

0.000795

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0390

Gnomad NFE exome

AF:

0.00609

Gnomad OTH exome

AF:

0.00687

GnomAD4 exome

AF:

0.00583

AC:

8522

AN:

1461872

Hom.:

Cov.:

AF XY:

0.00553

AC XY:

4018

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33480

American (AMR)

AF:

0.00195

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000459

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0419

AC:

2237

AN:

53400

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00526

AC:

5846

AN:

1112012

Other (OTH)

AF:

0.00522

AC:

315

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

552

1103

1655

2206

2758

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

206

412

618

824

1030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00584

AC:

882

AN:

151030

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

511

AN XY:

73628

show subpopulations

African (AFR)

AF:

0.000948

AC:

AN:

41118

American (AMR)

AF:

0.00232

AC:

AN:

15058

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4746

European-Finnish (FIN)

AF:

0.0388

AC:

403

AN:

10382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00580

AC:

393

AN:

67802

Other (OTH)

AF:

0.00431

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00485

Hom.:

Bravo

AF:

0.00292

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00559

AC:

ExAC

AF:

0.00623

AC:

756

EpiCase

AF:

0.00420

EpiControl

AF:

0.00522

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

KMT2A: BS2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 03, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 17, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:2

Dec 02, 2016

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0042

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.90

PhyloP100

3.5

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

REVEL

Benign

0.17

Sift

Uncertain

0.0080

Sift4G

Benign

0.26

Polyphen

0.69

Vest4

0.49

MVP

0.83

MPC

2.0

ClinPred

0.011

GERP RS

5.3

Varity_R

0.14

gMVP

0.40

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over