11-118436538-T-G

Variant names:

• chr11-118436538-T-G
• rs2134151980
• NM_001197104.2:c.26T>G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PP5_Moderate BP4

The NM_001197104.2(KMT2A):​c.26T>G​(p.Phe9Cys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F9L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.841
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a mutagenesis_site Loss of interaction with MEN1. (size 0) in uniprot entity KMT2A_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-118436538-T-G is Pathogenic according to our data. Variant chr11-118436538-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2637324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29147682). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.26T>G	p.Phe9Cys	missense_variant	Exon 1 of 36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.26T>G	p.Phe9Cys	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.-798-32237T>G		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

KMT2A-related disorder Pathogenic:1

Oct 07, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KMT2A c.26T>G variant is predicted to result in the amino acid substitution p.Phe9Cys. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. De novo variants in KMT2A are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Benign	0.81
DEOGEN2	Benign	0.27	.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	0.97	L;L;.;L
PhyloP100		0.84
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N;N;N;.
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;.
Polyphen		0.0020	.;B;B;.
Vest4		0.52
MutPred		0.21		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.94
MPC		1.1
ClinPred		0.60	D
GERP RS		2.3
PromoterAI		-0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.83
gMVP		0.55
Mutation Taster		=61/39	polymorphism

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: rs2134151980; hg19: chr11-118307253; COSMIC: COSV63291098; COSMIC: COSV63291098;