11-118519701-C-T

Position:

• chr11-118519701-C-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.11230C>T​(p.Arg3744Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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:4
• Conservation: PhyloP100: 3.23

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]

TTC36-AS1 (HGNC:55495): (TTC36 and KMT2A antisense RNA 1)

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 11-118519701-C-T is Pathogenic according to our data. Variant chr11-118519701-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 376783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.11230C>T	p.Arg3744Ter	stop_gained	32/36	ENST00000534358.8
TTC36-AS1	NR_120574.1	n.321+1565G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.11230C>T	p.Arg3744Ter	stop_gained	32/36	1	NM_001197104.2	P4
TTC36-AS1	ENST00000532597.6	n.241+1565G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 16, 2021	For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with KMT2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 376783). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg3744*) 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 06, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2018	The R3744X variant in the KMT2A gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R3744X variant is not observed in large population cohorts (Lek et al., 2016). We interpret R3744X as a pathogenic variant -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	KMT2A: PVS1, PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.69
GERP RS		0.94

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: rs1057520053; hg19: chr11-118390416; COSMIC: COSV63291284; COSMIC: COSV63291284;