11-118436594-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001197104.2(KMT2A):c.82G>T(p.Gly28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,173,506 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G28R) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.517

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18892518).

BS2

High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2 link	c.82G>T	p.Gly28Trp	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.82G>T	p.Gly28Trp	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2		Q03164-3
ENSG00000285827	ENST00000648261.1 link	c.-798-32181G>T		intron_variant	Intron 1 of 6			ENSP00000498126.1		A0A3B3ITZ1

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

149900

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

4442

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1023606

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

482866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

20768

American (AMR)

AF:

0.00

AC:

AN:

6608

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11808

East Asian (EAS)

AF:

0.00

AC:

AN:

21846

South Asian (SAS)

AF:

0.00

AC:

AN:

18908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2738

European-Non Finnish (NFE)

AF:

0.0000353

AC:

AN:

877006

Other (OTH)

AF:

0.00

AC:

AN:

39322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000133

AC:

AN:

149900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73180

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41094

American (AMR)

AF:

0.00

AC:

AN:

15082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3448

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

67316

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

ExAC

AF:

0.000238

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 27, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: KMT2A c.82G>T (p.Gly28Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 148682 control chromosomes (gnomAD v3.1.2). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.82G>T in individuals affected with Wiedemann-Steiner Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter has assessed the variant since 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 28 of the KMT2A protein (p.Gly28Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with KMT2A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1363232). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KMT2A protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.077

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

.;T;.;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.56

T;T;T;T

M_CAP

Pathogenic

0.79

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.55

N;N;.;N

PhyloP100

0.52

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.71

N;N;N;.

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D;D;.

Sift4G

Uncertain

0.0060

D;D;D;.

Polyphen

0.018, 0.57

.;B;P;.

Vest4

0.21

MutPred

0.34

Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);Gain of solvent accessibility (P = 0.0062);

MVP

0.57

MPC

0.94

ClinPred

0.44

GERP RS

0.66

PromoterAI

-0.096

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.45

gMVP

0.35

Mutation Taster

=84/16

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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11-118436594-G-T

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