rs1305215954

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001197104.2(KMT2A):c.58G>A(p.Gly20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 150,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22228071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2 link	c.58G>A	p.Gly20Ser	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.58G>A	p.Gly20Ser	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2		Q03164-3
ENSG00000285827	ENST00000648261.1 link	c.-798-32205G>A		intron_variant	Intron 1 of 6			ENSP00000498126.1		A0A3B3ITZ1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150854

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1040230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

491326

African (AFR)

AF:

0.00

AC:

AN:

21540

American (AMR)

AF:

0.00

AC:

AN:

7290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12554

East Asian (EAS)

AF:

0.00

AC:

AN:

23824

South Asian (SAS)

AF:

0.00

AC:

AN:

19190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3102

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

883334

Other (OTH)

AF:

0.00

AC:

AN:

40456

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150854

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73632

show subpopulations

African (AFR)

AF:

0.0000485

AC:

AN:

41268

American (AMR)

AF:

0.00

AC:

AN:

15160

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67620

Other (OTH)

AF:

0.00

AC:

AN:

2074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Jun 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KMT2A protein function. This variant has not been reported in the literature in individuals affected with KMT2A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 20 of the KMT2A protein (p.Gly20Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.17

.;T;.;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.40

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.58

T;T;T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.22

T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.90

L;L;.;L

PhyloP100

1.6

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.91

N;N;N;.

REVEL

Benign

0.18

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.032

D;T;D;.

Polyphen

0.038, 0.022

.;B;B;.

Vest4

0.29

MutPred

0.17

Gain of glycosylation at G20 (P = 0.0011);Gain of glycosylation at G20 (P = 0.0011);Gain of glycosylation at G20 (P = 0.0011);Gain of glycosylation at G20 (P = 0.0011);

MVP

0.59

MPC

0.79

ClinPred

0.53

GERP RS

1.1

PromoterAI

-0.050

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Varity_R

0.33

gMVP

0.32

Mutation Taster

=93/7

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1305215954

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over