rs781855910

chr11-118502413-C-Achr11-118502413-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001197104.2(KMT2A):c.6521C>A(p.Thr2174Asn) 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. 13/21 in silico tools predict a benign 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. T2174I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81

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 1 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=0.18215871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.6521C>A	p.Thr2174Asn	missense_variant	27/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.6521C>A	p.Thr2174Asn	missense_variant	27/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 130254

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Benign	23
Dann	Benign	0.88
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Uncertain	-0.27	T
MutationTaster	Benign	0.75	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.44	N;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D;.
Sift4G	Benign	0.58	T;T;.
Polyphen		0.63	.;P;.
Vest4		0.22
MutPred		0.088		.;Loss of glycosylation at T2171 (P = 0.0018);.;
MVP		0.63
MPC		0.82
ClinPred		0.26	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs781855910; hg19: chr11-118373128;