Variant 7-105040974-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_182931.3(KMT2E):c.22G>C(p.Gly8Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

KMT2E
NM_182931.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.01

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:

ENSG00000288914 (HGNC:):

ENSG00000288914 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2E	NM_182931.3 link	c.22G>C	p.Gly8Arg	missense_variant	3/27	ENST00000311117.8	NP_891847.1	Q8IZD2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KMT2E	ENST00000311117.8 link	c.22G>C	p.Gly8Arg	missense_variant	3/27	1	NM_182931.3	ENSP00000312379.3	Q8IZD2-1
ENSG00000288914	ENST00000688005.1 link	c.*18G>C		downstream_gene_variant				ENSP00000510606.1	A0A8I5QJV6
ENSG00000289360	ENST00000685210.1 link	c.*49G>C		downstream_gene_variant				ENSP00000510327.1	A0A8I5QJS6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461334

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727002

show subpopulations

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 12, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;T;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Pathogenic

0.75

D;D;D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Benign

1.7

L;L;.;.;L;.

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.5

D;D;D;D;D;D

REVEL

Pathogenic

0.65

Sift

Benign

0.083

T;T;D;T;T;T

Sift4G

Benign

0.12

T;T;D;T;T;T

Polyphen

0.29

B;B;.;.;B;.

Vest4

0.56

MutPred

0.57

Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);

MVP

0.84

MPC

0.66

ClinPred

0.88

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.52

gMVP

0.70

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over