Variant 11-118436543-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_001197104.2(KMT2A):c.31G>A(p.Ala11Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.1e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.74

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a mutagenesis_site Reduced interaction with MEN1. (size 0) in uniprot entity KMT2A_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, KMT2A

BP4

Computational evidence support a benign effect (MetaRNN=0.2966048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	1/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8 linkuse as main transcript	c.31G>A	p.Ala11Thr	missense_variant	1/36	1	NM_001197104.2	P4	Q03164-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

9.15e-7

AC:

AN:

1093032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

519640

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000800

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wiedemann-Steiner syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.77

T;T;T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.97

L;L;.;L

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-1.0

N;N;N;.

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.012

D;D;D;.

Polyphen

0.0010, 0.0030

.;B;B;.

Vest4

0.46

MutPred

0.20

Gain of phosphorylation at A11 (P = 0.0081);Gain of phosphorylation at A11 (P = 0.0081);Gain of phosphorylation at A11 (P = 0.0081);Gain of phosphorylation at A11 (P = 0.0081);

MVP

0.63

MPC

0.77

ClinPred

0.65

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.2

Varity_R

0.64

gMVP

0.53

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over