chr7-105110867-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_182931.3(KMT2E):ā€‹c.4067A>Cā€‹(p.Lys1356Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000249 in 1,606,912 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1356N) has been classified as Likely pathogenic.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

KMT2E
NM_182931.3 missense, splice_region

Scores

1
12
6
Splicing: ADA: 0.9990
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.34
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: 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.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KMT2ENM_182931.3 linkuse as main transcriptc.4067A>C p.Lys1356Thr missense_variant, splice_region_variant 26/27 ENST00000311117.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KMT2EENST00000311117.8 linkuse as main transcriptc.4067A>C p.Lys1356Thr missense_variant, splice_region_variant 26/271 NM_182931.3 P4Q8IZD2-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152250
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251084
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135702
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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
AF:
0.00000206
AC:
3
AN:
1454662
Hom.:
0
Cov.:
28
AF XY:
0.00000276
AC XY:
2
AN XY:
724258
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152250
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 01, 2022The c.4067A>C (p.K1356T) alteration is located in exon 26 (coding exon 24) of the KMT2E gene. This alteration results from a A to C substitution at nucleotide position 4067, causing the lysine (K) at amino acid position 1356 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.38
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.067
T;T
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.88
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.61
D;D
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.1
L;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.43
Sift
Pathogenic
0.0
D;D
Sift4G
Benign
0.10
T;T
Polyphen
1.0
D;D
Vest4
0.54
MutPred
0.33
Loss of methylation at K1356 (P = 2e-04);Loss of methylation at K1356 (P = 2e-04);
MVP
0.59
MPC
0.15
ClinPred
0.81
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.31
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.96
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1318743420; hg19: chr7-104751314; API