7-105062258-TA-T

Position:

• chr7-105062258-TA-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_182931.3(KMT2E):​c.167del​(p.Tyr56SerfsTer34) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2E NM_182931.3 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2E	NM_182931.3	c.167del	p.Tyr56SerfsTer34	frameshift_variant	4/27	ENST00000311117.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2E	ENST00000311117.8	c.167del	p.Tyr56SerfsTer34	frameshift_variant	4/27	1	NM_182931.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Feb 07, 2019

The heterozygous p.Tyr56Serfs*34 variant in KMT2E was identified by our study in one individual with intellectual disabilities and autism. The variant is assumed de novo, but maternity and paternity are not confirmed. The p.Tyr56Serfs*34 variant in KMT2E has not been previously reported in individuals with intellectual disabilities or autism and was absent from large population studies. However, this individual has been reported in a previous paper (Dong 2014, PMID: 25284784). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 56 and leads to a premature termination codon 34 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. It is of note, that loss of function of the KMT2E gene in autosomal dominant disease has not yet been established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

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: rs1584745301; hg19: chr7-104702705;