rs868985556

chr11-118478083-C-Gchr11-118478083-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate

The NM_001197104.2(KMT2A):c.3451C>G(p.Arg1151Gly) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1151Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 2 uncertain in NM_001197104.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-118478084-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 452735.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, KMT2A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.3451C>G	p.Arg1151Gly	missense_variant	5/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.3451C>G	p.Arg1151Gly	missense_variant	5/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.87	D
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.77, 0.69
MutPred		0.49		.;Loss of MoRF binding (P = 0.0345);Loss of MoRF binding (P = 0.0345);.;Loss of MoRF binding (P = 0.0345);.;
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.78
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-118348798;