chr11-118470934-T-C

Variant names:

• chr11-118470934-T-C
• rs7948661
• NM_001197104.2:c.503-728T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001197104.2(KMT2A):​c.503-728T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0615 in 152,262 control chromosomes in the GnomAD database, including 330 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.061 (330 hom., cov: 33)
• Consequence: KMT2A NM_001197104.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.752
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0764 is higher than 0.05.

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.503-728T>C		intron	N/A	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.602-728T>C		intron	N/A	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.503-728T>C		intron	N/A	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.503-728T>C		intron	N/A	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.503-728T>C		intron	N/A	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-728-728T>C		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 9343 AN: 152146 Hom.: 330 Cov.: 33

Gnomad AFR AF: 0.0784

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.0316

Gnomad SAS AF: 0.0663

Gnomad FIN AF: 0.0815

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0511

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0615 AC: 9360 AN: 152262 Hom.: 330 Cov.: 33 AF XY: 0.0620 AC XY: 4615 AN XY: 74446

African (AFR) AF: 0.0786 AC: 3268 AN: 41568

American (AMR) AF: 0.0364 AC: 556 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.0318 AC: 165 AN: 5184

South Asian (SAS) AF: 0.0667 AC: 322 AN: 4824

European-Finnish (FIN) AF: 0.0815 AC: 863 AN: 10594

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3897 AN: 68010

Other (OTH) AF: 0.0506 AC: 107 AN: 2116

Alfa AF: 0.0600 Hom.: 431

Bravo AF: 0.0598

Asia WGS AF: 0.0470 AC: 163 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.041
DANN	Benign	0.62
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs7948661; hg19: chr11-118341649;