rs629470

Positions:

• chr11-118449838-G-A
• chr11-118449838-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001197104.2(KMT2A):​c.432+12894G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,898 control chromosomes in the GnomAD database, including 4,758 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 0.23 (4758 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2A NM_001197104.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0320

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2A	NM_001197104.2	c.432+12894G>A		intron_variant		ENST00000534358.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2A	ENST00000534358.8	c.432+12894G>A		intron_variant		1	NM_001197104.2	P4

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34951 AN: 151780 Hom.: 4749 Cov.: 31

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.195

Gnomad EAS AF: 0.525

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.198

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.00

GnomAD4 genome AF: 0.230 AC: 34995 AN: 151898 Hom.: 4758 Cov.: 31 AF XY: 0.236 AC XY: 17551 AN XY: 74232

Gnomad4 AFR AF: 0.325

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.195

Gnomad4 EAS AF: 0.525

Gnomad4 SAS AF: 0.476

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.203

Alfa AF: 0.189 Hom.: 1722

Bravo AF: 0.226

Asia WGS AF: 0.491 AC: 1706 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	14
DANN	Benign	0.80

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: rs629470; hg19: chr11-118320553; COSMIC: COSV63281300;