Genetic Variant KMT2C:p.Ser4871Asn (chr7-152138827-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_170606.3(KMT2C):c.14612G>A(p.Ser4871Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

KMT2C
NM_170606.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.93

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2C	NM_170606.3 link	c.14612G>A	p.Ser4871Asn	missense_variant	Exon 58 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.14612G>A	p.Ser4871Asn	missense_variant	Exon 58 of 59	1	NM_170606.3	ENSP00000262189.6		Q8NEZ4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248100

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134000

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725370

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:

0.00

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

Jun 01, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter 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

0.74

BayesDel_addAF

Uncertain

0.090

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.52

D;D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.6

L;L;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.2

N;.;N

REVEL

Uncertain

0.53

Sift

Benign

0.032

D;.;T

Sift4G

Uncertain

0.034

.;.;D

Polyphen

1.0

D;D;.

Vest4

0.69

MutPred

0.64

Loss of catalytic residue at S4871 (P = 0.0278);Loss of catalytic residue at S4871 (P = 0.0278);.;

MVP

0.67

MPC

2.3

ClinPred

0.81

GERP RS

4.9

Varity_R

0.53

gMVP

0.89

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