rs7107305

Positions:

• chr11-118497950-A-G
• chr11-118497950-A-T

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.5679A>G​(p.Leu1893=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0569 in 1,610,442 control chromosomes in the GnomAD database, including 2,965 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: 0.058 (2780 hom.)
• Consequence: KMT2A NM_001197104.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.980

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=-0.54).
• BP6: Variant 11-118497950-A-G is Benign according to our data. Variant chr11-118497950-A-G is described in ClinVar as [Benign]. Clinvar id is 158705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-118497950-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.98 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.5679A>G	p.Leu1893=	synonymous_variant	21/36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.5679A>G	p.Leu1893=	synonymous_variant	21/36	1	NM_001197104.2	ENSP00000436786	P4

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6331 AN: 152168 Hom.: 185 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0255

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.0210

Gnomad SAS AF: 0.0672

Gnomad FIN AF: 0.0816

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0584

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0495 AC: 12447 AN: 251324 Hom.: 396 AF XY: 0.0527 AC XY: 7157 AN XY: 135830

Gnomad AFR exome AF: 0.00953

Gnomad AMR exome AF: 0.0225

Gnomad ASJ exome AF: 0.0525

Gnomad EAS exome AF: 0.0127

Gnomad SAS exome AF: 0.0748

Gnomad FIN exome AF: 0.0705

Gnomad NFE exome AF: 0.0583

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0585 AC: 85252 AN: 1458156 Hom.: 2780 Cov.: 30 AF XY: 0.0594 AC XY: 43121 AN XY: 725596

Gnomad4 AFR exome AF: 0.00864

Gnomad4 AMR exome AF: 0.0234

Gnomad4 ASJ exome AF: 0.0541

Gnomad4 EAS exome AF: 0.0309

Gnomad4 SAS exome AF: 0.0754

Gnomad4 FIN exome AF: 0.0658

Gnomad4 NFE exome AF: 0.0610

Gnomad4 OTH exome AF: 0.0549

GnomAD4 genome AF: 0.0416 AC: 6331 AN: 152286 Hom.: 185 Cov.: 32 AF XY: 0.0424 AC XY: 3161 AN XY: 74468

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.0212

Gnomad4 SAS AF: 0.0677

Gnomad4 FIN AF: 0.0816

Gnomad4 NFE AF: 0.0584

Gnomad4 OTH AF: 0.0342

Alfa AF: 0.0519 Hom.: 142

Bravo AF: 0.0363

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0563

EpiControl AF: 0.0572

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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+	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.76

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: rs7107305; hg19: chr11-118368665; COSMIC: COSV63283262; COSMIC: COSV63283262;