NM_001197104.2:c.2233C>T

Variant names:

• chr11-118473392-C-T
• rs727503777
• NM_001197104.2:c.2233C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001197104.2(KMT2A):​c.2233C>T​(p.Arg745*) 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: 31)
• Consequence: KMT2A NM_001197104.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.70
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Wiedemann-Steiner syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 11-118473392-C-T is Pathogenic according to our data. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118473392-C-T is described in CliVar as Pathogenic. Clinvar id is 180201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.2233C>T	p.Arg745*	stop_gained	Exon 3 of 36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.2233C>T	p.Arg745*	stop_gained	Exon 3 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.1003C>T	p.Arg335*	stop_gained	Exon 3 of 7			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Nov 05, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25574841) -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KMT2A: PVS1, PS2, PM2, PS4:Moderate -

Cornelia de Lange syndrome 1 Pathogenic:1

Dec 02, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		3.7
Vest4		0.91, 0.89
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727503777; hg19: chr11-118344107; COSMIC: COSV63281970;