Variant chr7-105110868-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_182931.3(KMT2E):c.4068G>C(p.Lys1356Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

KMT2E
NM_182931.3 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.80

Variant links:

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]

KMT2E links:

SRPK2 (HGNC:11306): (SRSF protein kinase 2) Enables ATP binding activity; magnesium ion binding activity; and protein serine/threonine kinase activity. Involved in several processes, including nucleic acid metabolic process; peptidyl-serine phosphorylation; and regulation of viral genome replication. Located in chromatin; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

SRPK2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-105110868-G-C is Pathogenic according to our data. Variant chr7-105110868-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2672119.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2E	NM_182931.3 link	c.4068G>C	p.Lys1356Asn	missense_variant, splice_region_variant	Exon 26 of 27	ENST00000311117.8	NP_891847.1	Q8IZD2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2E	ENST00000311117.8 link	c.4068G>C	p.Lys1356Asn	missense_variant, splice_region_variant	Exon 26 of 27	1	NM_182931.3	ENSP00000312379.3		Q8IZD2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

O'Donnell-Luria-Rodan syndrome

Pathogenic:1

Sep 02, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KMT2E c.4068G>C (p.Lys1356Asn) variant, to our knowledge, has not been reported in the medical literature and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This nucleotide change occurs in the last nucleotide of exon 26, a position that is highly conserved, and computational predictors indicate that this variant would alter splicing, evidence that correlates to an impact of this variant on KMT2E function. If exon 26 were skipped, this would result in an out of frame transcript predicted to result in a premature termination codon in the terminal exon. Several other variants predicted to result in a premature termination codon in the terminal exon have been described in affected individuals and are considered pathogenic (O'Donnell-Luria AH et al., PMID: 31079897). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.058

T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.26

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.1

L;L

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.088

T;T

Polyphen

1.0

D;D

Vest4

0.56

MutPred

0.32

Loss of methylation at K1356 (P = 2e-04);Loss of methylation at K1356 (P = 2e-04);

MVP

0.67

MPC

0.15

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.43

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.75

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.75

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over