11-118436601-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001197104.2(KMT2A):c.89C>G(p.Ala30Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0237 in 1,166,772 control chromosomes in the GnomAD database, including 397 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.015 ( 29 hom., cov: 32)

Exomes 𝑓: 0.025 ( 368 hom. )

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.13

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:

ENSG00000285827 (HGNC:):

ENSG00000285827 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 the KMT2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 124 curated benign missense variants. Gene score misZ: 6.2276 (above the threshold of 3.09). Trascript score misZ: 8.7715 (above the threshold of 3.09). GenCC associations: The gene is linked to Wiedemann-Steiner syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043572187).

BP6

Variant 11-118436601-C-G is Benign according to our data. Variant chr11-118436601-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 158711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118436601-C-G is described in Lovd as [Benign]. Variant chr11-118436601-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2276/149684) while in subpopulation NFE AF= 0.0243 (1635/67156). AF 95% confidence interval is 0.0234. There are 29 homozygotes in gnomad4. There are 1066 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2276 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2 link	c.89C>G	p.Ala30Gly	missense_variant	Exon 1 of 36	ENST00000534358.8	NP_001184033.1	Q03164-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8 link	c.89C>G	p.Ala30Gly	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2		Q03164-3
ENSG00000285827	ENST00000648261.1 link	c.-798-32174C>G		intron_variant	Intron 1 of 6			ENSP00000498126.1		A0A3B3ITZ1

Frequencies

GnomAD3 genomes

AF:

0.0152

AC:

2278

AN:

149574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00436

Gnomad AMI

AF:

0.0221

Gnomad AMR

AF:

0.00737

Gnomad ASJ

AF:

0.00232

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00457

Gnomad FIN

AF:

0.0282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0244

Gnomad OTH

AF:

0.0146

GnomAD3 exomes

AF:

0.0310

AC:

123

AN:

3974

Hom.:

AF XY:

0.0307

AC XY:

AN XY:

2084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0317

Gnomad NFE exome

AF:

0.0238

Gnomad OTH exome

AF:

0.0667

GnomAD4 exome

AF:

0.0250

AC:

25425

AN:

1017088

Hom.:

368

Cov.:

AF XY:

0.0249

AC XY:

11951

AN XY:

479602

show subpopulations

Gnomad4 AFR exome

AF:

0.00330

Gnomad4 AMR exome

AF:

0.00942

Gnomad4 ASJ exome

AF:

0.00329

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00509

Gnomad4 FIN exome

AF:

0.0278

Gnomad4 NFE exome

AF:

0.0272

Gnomad4 OTH exome

AF:

0.0198

GnomAD4 genome

AF:

0.0152

AC:

2276

AN:

149684

Hom.:

Cov.:

AF XY:

0.0146

AC XY:

1066

AN XY:

73118

show subpopulations

Gnomad4 AFR

AF:

0.00435

Gnomad4 AMR

AF:

0.00736

Gnomad4 ASJ

AF:

0.00232

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00458

Gnomad4 FIN

AF:

0.0282

Gnomad4 NFE

AF:

0.0243

Gnomad4 OTH

AF:

0.0139

Alfa

AF:

0.0181

Hom.:

Bravo

AF:

0.0133

ExAC

AF:

0.00824

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28386644) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2017

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 19, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Benign

0.92

DEOGEN2

Benign

0.13

.;T;.;.

Eigen

Benign

-0.040

Eigen_PC

Benign

-0.022

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.53

T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

-0.34

N;N;.;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.19

N;N;N;.

REVEL

Benign

0.17

Sift

Benign

0.076

T;T;D;.

Sift4G

Benign

0.17

T;T;T;.

Polyphen

0.95, 0.64

.;P;P;.

Vest4

0.17

MPC

0.80

ClinPred

0.18

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.17

gMVP

0.27

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