11-118503146-C-T

Variant names:

• chr11-118503146-C-T
• rs2071702
• NM_001197104.2:c.7254C>T

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.7254C>T​(p.Asn2418Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0632 in 1,613,462 control chromosomes in the GnomAD database, including 3,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (531 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3101 hom.)
• Consequence: KMT2A NM_001197104.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.541
• Publications: 17 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: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 11-118503146-C-T is Benign according to our data. Variant chr11-118503146-C-T is described in ClinVar as Benign. ClinVar VariationId is 158707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.541 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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.7254C>T	p.Asn2418Asn	synonymous	Exon 27 of 36	NP_001184033.1
	KMT2A	NM_001412597.1		c.7344C>T	p.Asn2448Asn	synonymous	Exon 28 of 37	NP_001399526.1
	KMT2A	NM_005933.4		c.7245C>T	p.Asn2415Asn	synonymous	Exon 27 of 36	NP_005924.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.7254C>T	p.Asn2418Asn	synonymous	Exon 27 of 36	ENSP00000436786.2
	KMT2A	ENST00000389506.10	TSL:1	c.7245C>T	p.Asn2415Asn	synonymous	Exon 27 of 36	ENSP00000374157.5
	KMT2A	ENST00000531904.7	TSL:2	c.7353C>T	p.Asn2451Asn	synonymous	Exon 28 of 37	ENSP00000432391.3

Frequencies

GnomAD3 genomes AF: 0.0729 AC: 11077 AN: 151956 Hom.: 526 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.0369

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.0666

Gnomad FIN AF: 0.0818

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0585

Gnomad OTH AF: 0.0507

GnomAD2 exomes AF: 0.0574 AC: 14411 AN: 250876 AF XY: 0.0585

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0524

Gnomad EAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0703

Gnomad NFE exome AF: 0.0584

Gnomad OTH exome AF: 0.0565

GnomAD4 exome AF: 0.0622 AC: 90921 AN: 1461388 Hom.: 3101 Cov.: 34 AF XY: 0.0626 AC XY: 45505 AN XY: 727006

African (AFR) AF: 0.121 AC: 4059 AN: 33474

American (AMR) AF: 0.0302 AC: 1352 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 1414 AN: 26132

East Asian (EAS) AF: 0.0303 AC: 1202 AN: 39700

South Asian (SAS) AF: 0.0752 AC: 6486 AN: 86232

European-Finnish (FIN) AF: 0.0655 AC: 3485 AN: 53172

Middle Eastern (MID) AF: 0.0562 AC: 324 AN: 5768

European-Non Finnish (NFE) AF: 0.0619 AC: 68809 AN: 1111800

Other (OTH) AF: 0.0628 AC: 3790 AN: 60390

GnomAD4 genome AF: 0.0730 AC: 11103 AN: 152074 Hom.: 531 Cov.: 32 AF XY: 0.0727 AC XY: 5404 AN XY: 74330

African (AFR) AF: 0.120 AC: 4980 AN: 41442

American (AMR) AF: 0.0369 AC: 563 AN: 15276

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

East Asian (EAS) AF: 0.0210 AC: 109 AN: 5182

South Asian (SAS) AF: 0.0670 AC: 323 AN: 4818

European-Finnish (FIN) AF: 0.0818 AC: 864 AN: 10562

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0585 AC: 3979 AN: 68010

Other (OTH) AF: 0.0501 AC: 106 AN: 2114

Alfa AF: 0.0633 Hom.: 219

Bravo AF: 0.0734

Asia WGS AF: 0.0470 AC: 162 AN: 3478

EpiCase AF: 0.0565

EpiControl AF: 0.0579

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.63
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs2071702; hg19: chr11-118373861; COSMIC: COSV63283268;