chr11-118436594-G-A

Variant names:

• chr11-118436594-G-A
• rs782113710
• NM_001197104.2:c.82G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001197104.2(KMT2A):​c.82G>A​(p.Gly28Arg) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G28W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.517
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25603616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.82G>A	p.Gly28Arg	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.82G>A	p.Gly28Arg	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.-798-32181G>A		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jul 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2A protein function. This variant has not been reported in the literature in individuals affected with KMT2A-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 28 of the KMT2A protein (p.Gly28Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.098	.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.55	T;T;T;T
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.55	N;N;.;N
PhyloP100		0.52
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.51	N;N;N;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.043	D;T;D;.
Polyphen		0.98, 1.0	.;D;D;.
Vest4		0.12
MutPred		0.27		Gain of methylation at G28 (P = 0.0071);Gain of methylation at G28 (P = 0.0071);Gain of methylation at G28 (P = 0.0071);Gain of methylation at G28 (P = 0.0071);
MVP		0.59
MPC		0.95
ClinPred		0.26	T
GERP RS		0.66
PromoterAI		-0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.39
gMVP		0.30
Mutation Taster		=75/25	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: rs782113710; hg19: chr11-118307309;