rs9332772

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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 criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.45

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2A. . Gene score misZ 6.2276 (greater than the threshold 3.09). Trascript score misZ 8.7715 (greater than threshold 3.09). GenCC has associacion of gene with Wiedemann-Steiner syndrome.

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]. Clinvar id is 211313.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118472663-G-A is described in Lovd as [Likely_benign]. Variant chr11-118472663-G-A is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 882 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2 linkuse as main transcript	c.1504G>A	p.Glu502Lys	missense_variant	3/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8 linkuse as main transcript	c.1504G>A	p.Glu502Lys	missense_variant	3/36	1	NM_001197104.2	P4	Q03164-3

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

GnomAD3 exomes

AF:

0.00663

AC:

1662

AN:

250866

Hom.:

AF XY:

0.00637

AC XY:

864

AN XY:

135630

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 SAS 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

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0419

Gnomad4 NFE exome

AF:

0.00526

Gnomad4 OTH exome

AF:

0.00522

GnomAD4 genome

AF:

0.00584

AC:

882

AN:

151030

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

511

AN XY:

73628

show subpopulations

Gnomad4 AFR

AF:

0.000948

Gnomad4 AMR

AF:

0.00232

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0388

Gnomad4 NFE

AF:

0.00580

Gnomad4 OTH

AF:

0.00431

Alfa

AF:

0.00456

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

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	KMT2A: BS1, BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 02, 2016	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

.;.;T;.;.

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.90

.;L;L;.;L

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.3

.;N;N;N;.

REVEL

Benign

0.17

Sift

Uncertain

0.0080

.;D;D;D;.

Sift4G

Benign

0.26

.;T;T;T;.

Polyphen

0.69, 0.82

.;.;P;P;.

Vest4

0.49, 0.43

MVP

0.83

MPC

2.0

ClinPred

0.011

GERP RS

5.3

Varity_R

0.14

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over