11-118436601-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001197104.2(KMT2A):c.89C>T(p.Ala30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000983 in 1,017,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A30G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KMT2A
• BP4: Computational evidence support a benign effect (MetaRNN=0.28974187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.89C>T	p.Ala30Val	missense_variant	1/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.89C>T	p.Ala30Val	missense_variant	1/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.83e-7 AC: 1 AN: 1017274 Hom.: 0 Cov.: 23 AF XY: 0.00000208 AC XY: 1 AN XY: 479688

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000430

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2021

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) performed at Invitae indicates that this missense variant is not expected to disrupt KMT2A protein function. This variant has not been reported in the literature in individuals 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 ExAC database. This sequence change replaces alanine with valine at codon 30 of the KMT2A protein (p.Ala30Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	0.032
Eigen_PC	Benign	0.026
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.60	T;T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N;N;.;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.54	N;N;N;.
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D;D;.
Sift4G	Uncertain	0.019	D;D;D;.
Polyphen		0.98, 0.81	.;D;P;.
Vest4		0.15
MutPred		0.23		Loss of methylation at R32 (P = 0.0923);Loss of methylation at R32 (P = 0.0923);Loss of methylation at R32 (P = 0.0923);Loss of methylation at R32 (P = 0.0923);
MVP		0.60
MPC		0.80
ClinPred		0.44	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.25
gMVP		0.41

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: chr11-118307316;