rs1555138487

Variant names:

• chr11-118436577-G-C
• rs1555138487
• NM_001197104.2:c.65G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001197104.2(KMT2A):​c.65G>C​(p.Gly22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000422 in 1,183,598 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.44
• 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

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24228892).

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.65G>C	p.Gly22Ala	missense	Exon 1 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.65G>C	p.Gly22Ala	missense	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.65G>C	p.Gly22Ala	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.65G>C	p.Gly22Ala	missense	Exon 1 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.65G>C	p.Gly22Ala	missense	Exon 1 of 36	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-798-32198G>C		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150610 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000387 AC: 4 AN: 1032988 Hom.: 0 Cov.: 20 AF XY: 0.00000820 AC XY: 4 AN XY: 487668

African (AFR) AF: 0.00 AC: 0 AN: 21246

American (AMR) AF: 0.00 AC: 0 AN: 6990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12352

East Asian (EAS) AF: 0.00 AC: 0 AN: 23186

South Asian (SAS) AF: 0.00 AC: 0 AN: 18972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2968

European-Non Finnish (NFE) AF: 0.00000455 AC: 4 AN: 879516

Other (OTH) AF: 0.00 AC: 0 AN: 40028

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150610 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73544

African (AFR) AF: 0.00 AC: 0 AN: 41252

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67540

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.81	L
PhyloP100		1.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.095
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.023	B
Vest4		0.16
MutPred		0.21		Loss of loop (P = 0.1242)
MVP		0.60
MPC		0.86
ClinPred		0.47	T
GERP RS		2.2
PromoterAI		-0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.30
gMVP		0.28
Mutation Taster		=90/10	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: rs1555138487; hg19: chr11-118307292;