7-152136899-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_170606.3(KMT2C):c.14669T>A(p.Phe4890Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2C NM_170606.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KMT2C

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2C	NM_170606.3	c.14669T>A	p.Phe4890Tyr	missense_variant	59/59	ENST00000262189.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2C	ENST00000262189.11	c.14669T>A	p.Phe4890Tyr	missense_variant	59/59	1	NM_170606.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2019

- -

Kleefstra syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Benign	0.93
DEOGEN2	Uncertain	0.46	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	0.39	N;N;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	D;.;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.019	D;.;T
Polyphen		0.99	D;D;.
Vest4		0.65
MutPred		0.53		Gain of ubiquitination at K4887 (P = 0.0716);Gain of ubiquitination at K4887 (P = 0.0716);.;
MVP		0.92
MPC		2.5
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.35
gMVP		0.60

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

Other links and lift over

dbSNP: rs2089918301; hg19: chr7-151833984;