Genetic Variant KMT2C:p.Gly845Glu (chr7-152238825-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_170606.3(KMT2C):c.2534G>A(p.Gly845Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0060 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2C
NM_170606.3 missense, splice_region

Scores

Splicing: ADA: 0.9962

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.31

Variant links:

Genes affected

KMT2C (HGNC:13726): (lysine methyltransferase 2C) This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]

KMT2C links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

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 rank	MANE	Protein	UniProt
KMT2C	NM_170606.3 link	c.2534G>A	p.Gly845Glu	missense_variant, splice_region_variant	Exon 15 of 59	ENST00000262189.11	NP_733751.2	Q8NEZ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2C	ENST00000262189.11 link	c.2534G>A	p.Gly845Glu	missense_variant, splice_region_variant	Exon 15 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

609

AN:

102386

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00548

Gnomad AMI

AF:

0.00692

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00588

Gnomad EAS

AF:

0.00181

Gnomad SAS

AF:

0.00775

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00460

Gnomad OTH

AF:

0.00346

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00633

AC:

6364

AN:

1005800

Hom.:

Cov.:

AF XY:

0.00580

AC XY:

2953

AN XY:

509428

show subpopulations

Gnomad4 AFR exome

AF:

0.00398

Gnomad4 AMR exome

AF:

0.00672

Gnomad4 ASJ exome

AF:

0.00319

Gnomad4 EAS exome

AF:

0.00257

Gnomad4 SAS exome

AF:

0.00223

Gnomad4 FIN exome

AF:

0.00213

Gnomad4 NFE exome

AF:

0.00729

Gnomad4 OTH exome

AF:

0.00613

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00599

AC:

613

AN:

102412

Hom.:

Cov.:

AF XY:

0.00724

AC XY:

360

AN XY:

49700

show subpopulations

Gnomad4 AFR

AF:

0.00554

Gnomad4 AMR

AF:

0.0109

Gnomad4 ASJ

AF:

0.00588

Gnomad4 EAS

AF:

0.00182

Gnomad4 SAS

AF:

0.00807

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.00460

Gnomad4 OTH

AF:

0.00413

Alfa

AF:

0.0268

Hom.:

ExAC

AF:

0.0579

AC:

7026

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

.;D

MetaRNN

Benign

0.0064

T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.55

Sift

Uncertain

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.73

MPC

2.7

ClinPred

0.013

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.61

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over