7-105062228-T-C

Position:

• chr7-105062228-T-C

Variant summary

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

The NM_182931.3(KMT2E):​c.136T>C​(p.Tyr46His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,402 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KMT2E NM_182931.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

Genes affected

KMT2E (HGNC:18541): (lysine methyltransferase 2E (inactive)) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a protein with an N-terminal PHD zinc finger and a central SET domain. Overexpression of the protein inhibits cell cycle progression. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4020894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2E	NM_182931.3	c.136T>C	p.Tyr46His	missense_variant	4/27	ENST00000311117.8	NP_891847.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2E	ENST00000311117.8	c.136T>C	p.Tyr46His	missense_variant	4/27	1	NM_182931.3	ENSP00000312379.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461402 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727024

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: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.0000166

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

Labcorp Genetics (formerly Invitae), Labcorp

Oct 15, 2023

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 46 of the KMT2E protein (p.Tyr46His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KMT2E-related conditions. 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 KMT2E protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	0.58	D
MutationAssessor	Benign	0.74	N;N;.;N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.027	D;D;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.52
MutPred		0.19		Loss of phosphorylation at Y46 (P = 0.0376);Loss of phosphorylation at Y46 (P = 0.0376);Loss of phosphorylation at Y46 (P = 0.0376);Loss of phosphorylation at Y46 (P = 0.0376);Loss of phosphorylation at Y46 (P = 0.0376);
MVP		0.74
MPC		1.1
ClinPred		0.85	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.14
gMVP		0.50

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: rs1796843653; hg19: chr7-104702675;