11-118436670-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001197104.2(KMT2A):c.158C>T(p.Ala53Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,220,738 control chromosomes in the GnomAD database, including 106 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 0.0065 ( 54 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 52 hom. )

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.0170

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=0.0011565089).

BP6

Variant 11-118436670-C-T is Benign according to our data. Variant chr11-118436670-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 252562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2 link	c.158C>T	p.Ala53Val	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.158C>T	p.Ala53Val	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2		Q03164-3
ENSG00000285827	ENST00000648261.1 link	c.-798-32105C>T		intron_variant	Intron 1 of 6			ENSP00000498126.1		A0A3B3ITZ1

Frequencies

GnomAD3 genomes

AF:

0.00647

AC:

965

AN:

149140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00149

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.000290

Gnomad EAS

AF:

0.00295

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000552

Gnomad OTH

AF:

0.00684

GnomAD3 exomes

AF:

0.00256

AC:

AN:

6630

Hom.:

AF XY:

0.00241

AC XY:

AN XY:

3318

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.462

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000683

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.00111

AC:

1184

AN:

1071488

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

540

AN XY:

509898

show subpopulations

Gnomad4 AFR exome

AF:

0.000503

Gnomad4 AMR exome

AF:

0.0929

Gnomad4 ASJ exome

AF:

0.00145

Gnomad4 EAS exome

AF:

0.00367

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.00117

Gnomad4 NFE exome

AF:

0.000207

Gnomad4 OTH exome

AF:

0.00300

GnomAD4 genome

AF:

0.00650

AC:

970

AN:

149250

Hom.:

Cov.:

AF XY:

0.00697

AC XY:

508

AN XY:

72844

show subpopulations

Gnomad4 AFR

AF:

0.00148

Gnomad4 AMR

AF:

0.0553

Gnomad4 ASJ

AF:

0.000290

Gnomad4 EAS

AF:

0.00296

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.000552

Gnomad4 OTH

AF:

0.00676

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.0122

ExAC

AF:

0.00328

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 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

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 04, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

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

0.15

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

.;T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.59

T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.34

N;N;.;N

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.37

N;N;N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.030

D;D;D;.

Polyphen

0.89, 0.96

.;P;D;.

Vest4

0.074

MVP

0.58

MPC

0.80

ClinPred

0.093

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.14

gMVP

0.35

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