rs576950

Positions:

• chr11-118520660-A-G
• chr11-118520660-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001197104.2(KMT2A):​c.11430-142A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.355 in 602,186 control chromosomes in the GnomAD database, including 41,604 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (9220 hom., cov: 29)
  • Exomes 𝑓: 0.37 (32384 hom.)
• Consequence: KMT2A NM_001197104.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.25

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 11-118520660-A-G is Benign according to our data. Variant chr11-118520660-A-G is described in ClinVar as [Benign]. Clinvar id is 1242710.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.11430-142A>G		intron_variant		ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.11430-142A>G		intron_variant		1	NM_001197104.2	ENSP00000436786.2

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47766 AN: 151434 Hom.: 9225 Cov.: 29

Gnomad AFR AF: 0.0922

Gnomad AMI AF: 0.333

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.452

Gnomad EAS AF: 0.185

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.441

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.368 AC: 166045 AN: 450634 Hom.: 32384 Cov.: 5 AF XY: 0.363 AC XY: 85830 AN XY: 236756

Gnomad4 AFR exome AF: 0.0892

Gnomad4 AMR exome AF: 0.313

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.154

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.370

GnomAD4 genome AF: 0.315 AC: 47750 AN: 151552 Hom.: 9220 Cov.: 29 AF XY: 0.311 AC XY: 23034 AN XY: 74022

Gnomad4 AFR AF: 0.0919

Gnomad4 AMR AF: 0.353

Gnomad4 ASJ AF: 0.452

Gnomad4 EAS AF: 0.186

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.380

Gnomad4 NFE AF: 0.441

Gnomad4 OTH AF: 0.357

Alfa AF: 0.391 Hom.: 14080

Bravo AF: 0.304

Asia WGS AF: 0.192 AC: 667 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.32
DANN	Benign	0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs576950; hg19: chr11-118391375;