rs886041896

chr11-118494360-A-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001197104.2(KMT2A):c.5251A>T(p.Lys1751Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.75

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 11-118494360-A-T is Pathogenic according to our data. Variant chr11-118494360-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 280748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118494360-A-T is described in Lovd as [Likely_pathogenic]. Variant chr11-118494360-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.5251A>T	p.Lys1751Ter	stop_gained	17/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.5251A>T	p.Lys1751Ter	stop_gained	17/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 10, 2017

- -

Wiedemann-Steiner syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Oct 30, 2023

The KMT2A c.5251A>T (p.Lys1751Ter) variant has been reported in several individuals affected with neurodevelopmental disorders (Foroutan A et al., PMID: 35163737; Sheppard SE et al., PMID: 33783954; Trujillano D et al., PMID: 27848944; Wang T et al. Nat Commun., PMID: 33004838). This variant has been reported in the ClinVar database as a germline pathogenic variant by two submitters. This variant is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2021

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27848944, 28191889) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.92
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs886041896; hg19: chr11-118365075; COSMIC: COSV63285844; COSMIC: COSV63285844;