rs9332801

Positions:

• chr11-118484927-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001197104.2(KMT2A):​c.4284A>C​(p.Ile1428=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0571 in 1,613,484 control chromosomes in the GnomAD database, including 2,973 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (185 hom., cov: 32)
  • Exomes 𝑓: 0.059 (2788 hom.)
• Consequence: KMT2A NM_001197104.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.77

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 11-118484927-A-C is Benign according to our data. Variant chr11-118484927-A-C is described in ClinVar as [Benign]. Clinvar id is 158702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118484927-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.4284A>C	p.Ile1428=	synonymous_variant	10/36	ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.4284A>C	p.Ile1428=	synonymous_variant	10/36	1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6321 AN: 152174 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0472

Gnomad EAS AF: 0.0310

Gnomad SAS AF: 0.0678

Gnomad FIN AF: 0.0817

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0574

Gnomad OTH AF: 0.0353

GnomAD3 exomes AF: 0.0500 AC: 12569 AN: 251238 Hom.: 401 AF XY: 0.0532 AC XY: 7230 AN XY: 135780

Gnomad AFR exome AF: 0.00953

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0526

Gnomad EAS exome AF: 0.0234

Gnomad SAS exome AF: 0.0754

Gnomad FIN exome AF: 0.0702

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0514

GnomAD4 exome AF: 0.0588 AC: 85866 AN: 1461192 Hom.: 2788 Cov.: 30 AF XY: 0.0598 AC XY: 43453 AN XY: 726904

Gnomad4 AFR exome AF: 0.00863

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0541

Gnomad4 EAS exome AF: 0.0469

Gnomad4 SAS exome AF: 0.0763

Gnomad4 FIN exome AF: 0.0654

Gnomad4 NFE exome AF: 0.0608

Gnomad4 OTH exome AF: 0.0550

GnomAD4 genome AF: 0.0415 AC: 6321 AN: 152292 Hom.: 185 Cov.: 32 AF XY: 0.0426 AC XY: 3169 AN XY: 74462

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0472

Gnomad4 EAS AF: 0.0312

Gnomad4 SAS AF: 0.0683

Gnomad4 FIN AF: 0.0817

Gnomad4 NFE AF: 0.0574

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0538 Hom.: 243

Bravo AF: 0.0363

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.0559

EpiControl AF: 0.0570

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.5
DANN	Benign	0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs9332801; hg19: chr11-118355642; COSMIC: COSV63283256; COSMIC: COSV63283256;