NM_001197104.2:c.63_65dupCGG

Variant names:

• chr11-118436563-G-GGGC
• rs1407741917
• NM_001197104.2:c.63_65dupCGG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_001197104.2(KMT2A):​c.63_65dupCGG​(p.Gly22dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,052,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KMT2A NM_001197104.2 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.579
• 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
• PM4: Nonframeshift variant in NON repetitive region in NM_001197104.2. Strenght limited to Supporting due to length of the change: 1aa.

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.63_65dupCGG	p.Gly22dup	disruptive_inframe_insertion	Exon 1 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.63_65dupCGG	p.Gly22dup	disruptive_inframe_insertion	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.63_65dupCGG	p.Gly22dup	disruptive_inframe_insertion	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.63_65dupCGG	p.Gly22dup	disruptive_inframe_insertion	Exon 1 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.63_65dupCGG	p.Gly22dup	disruptive_inframe_insertion	Exon 1 of 36	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-798-32200_-798-32198dupCGG		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1052354 Hom.: 0 Cov.: 19 AF XY: 0.00000201 AC XY: 1 AN XY: 497844

African (AFR) AF: 0.00 AC: 0 AN: 22112

American (AMR) AF: 0.00 AC: 0 AN: 8112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12752

East Asian (EAS) AF: 0.00 AC: 0 AN: 24810

South Asian (SAS) AF: 0.00 AC: 0 AN: 19822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3344

European-Non Finnish (NFE) AF: 0.00000337 AC: 3 AN: 889736

Other (OTH) AF: 0.00 AC: 0 AN: 41042

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1407741917; hg19: chr11-118307278;