Genetic Variant NM_001197104.2:c.5494C>A (chr11-118495830-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_001197104.2(KMT2A):c.5494C>A(p.Pro1832Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2A
NM_001197104.2 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.92

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-118495830-C-A is Pathogenic according to our data. Variant chr11-118495830-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 209168.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.3364471). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2A	NM_001197104.2	MANE Select	c.5494C>A	p.Pro1832Thr	missense	Exon 19 of 36	NP_001184033.1
KMT2A	NM_001412597.1		c.5584C>A	p.Pro1862Thr	missense	Exon 20 of 37	NP_001399526.1
KMT2A	NM_005933.4		c.5485C>A	p.Pro1829Thr	missense	Exon 19 of 36	NP_005924.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.5494C>A	p.Pro1832Thr	missense	Exon 19 of 36	ENSP00000436786.2
KMT2A	ENST00000389506.10	TSL:1	c.5485C>A	p.Pro1829Thr	missense	Exon 19 of 36	ENSP00000374157.5
KMT2A	ENST00000531904.7	TSL:2	c.5593C>A	p.Pro1865Thr	missense	Exon 20 of 37	ENSP00000432391.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Wiedemann-Steiner syndrome

Pathogenic:1

Oct 11, 2013

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Likely pathogenicity based on finding it once in our laboratory de novo in a 19-year-old female with hypertrophic cardiomyopathy, polyneuropathy, chorea, epilepsy, delayed puberty, PCOS, osteopenia, mild intellectual disability, hypertrichosis, Asperger syndrome, attention deficit, anxiety, strabismus, dysmorphisms

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Uncertain

0.035

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.34

MetaSVM

Uncertain

-0.087

MutationAssessor

Benign

1.9

PhyloP100

3.9

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.37

Sift

Uncertain

0.014

Sift4G

Uncertain

0.013

Polyphen

0.55

Vest4

0.29

MutPred

0.22

Gain of phosphorylation at P1829 (P = 0.0051)

MVP

0.52

MPC

1.5

ClinPred

0.92

GERP RS

4.4

Varity_R

0.41

gMVP

0.56

Mutation Taster

=62/38

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over