Genetic Variant KMT2A:p.Cys5Tyr (chr11-118436526-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001197104.2(KMT2A):c.14G>A(p.Cys5Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000009 in 1,110,642 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C5S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.81

Publications

0 publications found

Variant links:

Genes affected

KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

KMT2A Gene-Disease associations (from GenCC):

Wiedemann-Steiner syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

KMT2A links:

ENSG00000285827 (HGNC:):

ENSG00000285827 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
KMT2A	NM_001197104.2 link	c.14G>A	p.Cys5Tyr	missense_variant	Exon 1 of 36	ENST00000534358.8	NP_001184033.1	Q03164-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8 link	c.14G>A	p.Cys5Tyr	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2		Q03164-3
ENSG00000285827	ENST00000648261.1 link	c.-798-32249G>A		intron_variant	Intron 1 of 6			ENSP00000498126.1		A0A3B3ITZ1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.00e-7

AC:

AN:

1110642

Hom.:

Cov.:

AF XY:

0.00000189

AC XY:

AN XY:

529374

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

23516

American (AMR)

AF:

0.00

AC:

AN:

14546

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13586

East Asian (EAS)

AF:

0.00

AC:

AN:

27780

South Asian (SAS)

AF:

0.00

AC:

AN:

23328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3724

European-Non Finnish (NFE)

AF:

0.00000108

AC:

AN:

925696

Other (OTH)

AF:

0.00

AC:

AN:

43270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

.;T;.;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Pathogenic

0.96

MetaRNN

Uncertain

0.63

D;D;D;D

MetaSVM

Uncertain

0.19

MutationAssessor

Benign

0.90

L;L;.;L

PhyloP100

1.8

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-2.5

N;N;N;.

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.010

D;D;D;.

Polyphen

0.94

.;P;P;.

Vest4

0.18

MutPred

0.42

Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);

MVP

0.88

MPC

1.3

ClinPred

0.89

GERP RS

3.6

PromoterAI

0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.86

gMVP

0.54

Mutation Taster

=62/38

polymorphism

(source)

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

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11-118436526-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over