NM_001197104.2:c.5679A>G

Variant names:

• chr11-118497950-A-G
• rs7107305
• NM_001197104.2:c.5679A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001197104.2(KMT2A):​c.5679A>G​(p.Leu1893Leu) 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
• Publications: 16 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 158705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.5679A>G	p.Leu1893Leu	synonymous	Exon 21 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.5769A>G	p.Leu1923Leu	synonymous	Exon 22 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.5670A>G	p.Leu1890Leu	synonymous	Exon 21 of 36	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.5679A>G	p.Leu1893Leu	synonymous	Exon 21 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.5670A>G	p.Leu1890Leu	synonymous	Exon 21 of 36	ENSP00000374157.5	Q03164-1
	KMT2A	ENST00000531904.7	TSL:2	c.5778A>G	p.Leu1926Leu	synonymous	Exon 22 of 37	ENSP00000432391.3	E9PR05

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

GnomAD2 exomes AF: 0.0495 AC: 12447 AN: 251324 AF XY: 0.0527

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 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

African (AFR) AF: 0.00864 AC: 289 AN: 33446

American (AMR) AF: 0.0234 AC: 1046 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 1411 AN: 26096

East Asian (EAS) AF: 0.0309 AC: 1227 AN: 39668

South Asian (SAS) AF: 0.0754 AC: 6497 AN: 86138

European-Finnish (FIN) AF: 0.0658 AC: 3513 AN: 53394

Middle Eastern (MID) AF: 0.0501 AC: 289 AN: 5764

European-Non Finnish (NFE) AF: 0.0610 AC: 67671 AN: 1108682

Other (OTH) AF: 0.0549 AC: 3309 AN: 60258

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

African (AFR) AF: 0.0102 AC: 425 AN: 41580

American (AMR) AF: 0.0254 AC: 389 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0473 AC: 164 AN: 3468

East Asian (EAS) AF: 0.0212 AC: 110 AN: 5184

South Asian (SAS) AF: 0.0677 AC: 327 AN: 4830

European-Finnish (FIN) AF: 0.0816 AC: 865 AN: 10600

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0584 AC: 3969 AN: 68010

Other (OTH) AF: 0.0342 AC: 72 AN: 2108

Alfa AF: 0.0510 Hom.: 174

Bravo AF: 0.0363

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.0563

EpiControl AF: 0.0572

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.9
DANN	Benign	0.76
PhyloP100		0.98
PromoterAI		0.012	Neutral
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: rs7107305; hg19: chr11-118368665; COSMIC: COSV63283262;