11-118503987-C-G

Variant names:

• chr11-118503987-C-G
• rs587783680
• NM_001197104.2:c.8095C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001197104.2(KMT2A):​c.8095C>G​(p.Arg2699Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2699Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.46
• 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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.8095C>G	p.Arg2699Gly	missense	Exon 27 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.8185C>G	p.Arg2729Gly	missense	Exon 28 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.8086C>G	p.Arg2696Gly	missense	Exon 27 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.8095C>G	p.Arg2699Gly	missense	Exon 27 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.8086C>G	p.Arg2696Gly	missense	Exon 27 of 36	ENSP00000374157.5	Q03164-1
	KMT2A	ENST00000531904.7	TSL:2	c.8194C>G	p.Arg2732Gly	missense	Exon 28 of 37	ENSP00000432391.3	E9PR05

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.29	T
MutationAssessor	Benign	1.7	L
PhyloP100		2.5
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.52	N
REVEL	Uncertain	0.54
Sift	Benign	0.082	T
Sift4G	Benign	0.27	T
Polyphen		0.96	D
Vest4		0.65
MutPred		0.60		Loss of helix (P = 0.0558)
MVP		0.96
MPC		1.2
ClinPred		0.75	D
GERP RS		5.5
Varity_R		0.11
gMVP		0.45
Mutation Taster		=64/36	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: rs587783680; hg19: chr11-118374702;