Variant rs398122878 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001197104.2(KMT2A):c.8806_8809del(p.Val2936Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2A
NM_001197104.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.67

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-118504690-ATCTG-A is Pathogenic according to our data. Variant chr11-118504690-ATCTG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37071.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-118504690-ATCTG-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2 linkuse as main transcript	c.8806_8809del	p.Val2936Ter	frameshift_variant	27/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8 linkuse as main transcript	c.8806_8809del	p.Val2936Ter	frameshift_variant	27/36	1	NM_001197104.2	P4	Q03164-3

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wiedemann-Steiner syndrome

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 10, 2012

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 27, 2023

This sequence change creates a premature translational stop signal (p.Val2936*) in the KMT2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2A are known to be pathogenic (PMID: 22795537, 25574841, 25810209, 28120103, 29574747, 31157197, 31337854). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Wiedemann-Steiner syndrome (PMID: 22795537, 30287924). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing