11-118472592-G-A

Position:

• chr11-118472592-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001197104.2(KMT2A):​c.1433G>A​(p.Arg478Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,884 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.16

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]

ENSG00000285827 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2A. . Gene score misZ 6.2276 (greater than the threshold 3.09). Trascript score misZ 8.7715 (greater than threshold 3.09). GenCC has associacion of gene with Wiedemann-Steiner syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3396721).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.1433G>A	p.Arg478Gln	missense_variant	3/36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.1433G>A	p.Arg478Gln	missense_variant	3/36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.203G>A	p.Arg68Gln	missense_variant	3/7			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461884 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wiedemann-Steiner syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it once in our laboratory de novo in a 1-year-old female with IUGR, global delays, conductive hearing loss, hypotonia, dysmorphisms, microcephaly, failure to thrive, PDA, cleft palate -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 01, 2024

Not observed at significant frequency in large population cohorts (gnomAD); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25326635, 35727845) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;.;T;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.34	T;T;T;T;T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Benign	1.1	.;L;L;.;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.83	.;N;N;N;.
REVEL	Benign	0.25
Sift	Uncertain	0.0020	.;D;D;D;.
Sift4G	Benign	0.28	.;T;T;T;.
Polyphen		1.0	.;.;D;D;.
Vest4		0.69, 0.47
MutPred		0.14		.;Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;Gain of relative solvent accessibility (P = 0.0479);
MVP		0.85
MPC		2.0
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.53

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: rs782711809; hg19: chr11-118343307;