11-118473470-AC-ACC

Position:

• chr11-118473470-AC-ACC

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001197104.2(KMT2A):​c.2318dupC​(p.Ser774fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000547 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: KMT2A NM_001197104.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 3.61

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]

ENSG00000285827 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-118473470-A-AC is Pathogenic according to our data. Variant chr11-118473470-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 374257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.2318dupC	p.Ser774fs	frameshift_variant	3/36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.2318dupC	p.Ser774fs	frameshift_variant	3/36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.1088dupC	p.Ser364fs	frameshift_variant	3/7			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461736 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wiedemann-Steiner syndrome Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 09, 2022	ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting, PM6 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Baylor Genetics	Mar 26, 2015	Our laboratory reported dual molecular diagnoses in ARID1B (NM_017519.2, c.17G>A) and KMT2A (NM_005933.2, c.2318dup) in one individual with reported features of delayed motor milestones, delayed speech, intellectual disability, hypotonia, double jointed, strabismus, bicuspid aortic valve and inferior urethra. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Aug 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.2318dup;p.(Ser774Valfs*12) is a null frameshift variant (NMD) in the KMT2A gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 374257; PMID: 29574747; 28600779) - PS4. This variant is not present in population databases (rs782297546, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4_Moderate+PS2 -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	This sequence change creates a premature translational stop signal (p.Ser774Valfs*12) 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, 25810209, 29574747). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with features of autism spectrum disorder and in two individuals undergoing diagnostic exome sequencing (PMID: 25356970, 28330790). ClinVar contains an entry for this variant (Variation ID: 374257). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 03, 2018	DNA sequence analysis of the KMT2A gene demonstrated a one base pair duplication in exon 3, c.2318dup. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 11 amino acids downstream of the variant, p.Ser774Valfs*12. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated KMT2A protein with potentially abnormal function. This pathogenic sequence change has previously been described as a de novo variant in a patient with Wiedemann-Steiner syndrome (Farwell et. al., 2014). This pathogenic sequence change is the most likely cause of this phenotype. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2022	Frameshift variant predicted to result in nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25356970, 27959697, 29574747, 34102828, 33043602, 28330790, 33783954, 33004838, 30305169) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2017

- -

Adrenal cortex carcinoma Other:1

-, no assertion criteria provided

research

Genome Sciences Centre, British Columbia Cancer Agency

Nov 13, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs782297546; hg19: chr11-118344185;