rs1555038125

Variant names:

• chr11-118478198-G-A
• rs1555038125
• NM_001197104.2:c.3566G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001197104.2(KMT2A):​c.3566G>A​(p.Cys1189Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.94

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 10 ACMG points.

• PM1: In a mutagenesis_site Abolishes zinc-binding and stability of the CXXC-type zinc finger and causes loss of DNA-binding. (size 0) in uniprot entity KMT2A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KMT2A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 124 curated benign missense variants. Gene score misZ: 6.2276 (above the threshold of 3.09). Trascript score misZ: 8.7715 (above the threshold of 3.09). GenCC associations: The gene is linked to Wiedemann-Steiner syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-118478198-G-A is Pathogenic according to our data. Variant chr11-118478198-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 523095.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr11-118478198-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.3566G>A	p.Cys1189Tyr	missense_variant	Exon 5 of 36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.3566G>A	p.Cys1189Tyr	missense_variant	Exon 5 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.2336G>A	p.Cys779Tyr	missense_variant	Exon 5 of 7			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Wiedemann-Steiner syndrome Pathogenic:1

Apr 27, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;.;D;.;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.62	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	.;M;M;.;M;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.1	.;D;D;D;.;.
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D;D;D;.;.
Sift4G	Pathogenic	0.0010	.;D;D;D;.;.
Polyphen		1.0	.;.;D;.;.;.
Vest4		0.94, 0.94
MutPred		0.87		.;Loss of methylation at K1190 (P = 0.0465);Loss of methylation at K1190 (P = 0.0465);.;Loss of methylation at K1190 (P = 0.0465);.;
MVP		0.97
MPC		2.4
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

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: rs1555038125; hg19: chr11-118348913;