rs782207243

Variant names:

• chr11-118436539-C-A
• rs782207243
• NM_001197104.2:c.27C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-118436539-C-A
• chr11-118436539-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001197104.2(KMT2A):​c.27C>A​(p.Phe9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F9C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

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: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ENSG00000285827 (HGNC:):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-118436538-T-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2637324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32909724).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	NM_001197104.2	MANE Select	c.27C>A	p.Phe9Leu	missense	Exon 1 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.27C>A	p.Phe9Leu	missense	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.27C>A	p.Phe9Leu	missense	Exon 1 of 36	NP_005924.2	Q03164-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.27C>A	p.Phe9Leu	missense	Exon 1 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.27C>A	p.Phe9Leu	missense	Exon 1 of 36	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-798-32236C>A		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1094702 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 520620

African (AFR) AF: 0.00 AC: 0 AN: 23216

American (AMR) AF: 0.00 AC: 0 AN: 12818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13284

East Asian (EAS) AF: 0.00 AC: 0 AN: 27038

South Asian (SAS) AF: 0.00 AC: 0 AN: 22222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3664

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 916162

Other (OTH) AF: 0.00 AC: 0 AN: 42628

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.047
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.71	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	0.97	L
PhyloP100		2.3
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.052	T
Polyphen		0.23	B
Vest4		0.32
MutPred		0.26		Loss of sheet (P = 0.1158)
MVP		0.85
MPC		0.93
ClinPred		0.76	D
GERP RS		3.6
PromoterAI		-0.091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.89
gMVP		0.47
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

dbSNP: rs782207243; hg19: chr11-118307254; COSMIC: COSV63292741;