rs9332801

Variant names:

• chr11-118484927-A-C
• rs9332801
• NM_001197104.2:c.4284A>C

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.4284A>C​(p.Ile1428Ile) 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:7
• Conservation: PhyloP100: 1.77
• 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: 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=-0.51).
• BP6: Variant 11-118484927-A-C is Benign according to our data. Variant chr11-118484927-A-C is described in ClinVar as Benign. ClinVar VariationId is 158702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.4284A>C	p.Ile1428Ile	synonymous	Exon 10 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.4383A>C	p.Ile1461Ile	synonymous	Exon 11 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.4284A>C	p.Ile1428Ile	synonymous	Exon 10 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.4284A>C	p.Ile1428Ile	synonymous	Exon 10 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.4284A>C	p.Ile1428Ile	synonymous	Exon 10 of 36	ENSP00000374157.5	Q03164-1
	KMT2A	ENST00000531904.7	TSL:2	c.4383A>C	p.Ile1461Ile	synonymous	Exon 11 of 37	ENSP00000432391.3	E9PR05

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

GnomAD2 exomes AF: 0.0500 AC: 12569 AN: 251238 AF XY: 0.0532

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 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

African (AFR) AF: 0.00863 AC: 289 AN: 33472

American (AMR) AF: 0.0229 AC: 1023 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0541 AC: 1414 AN: 26126

East Asian (EAS) AF: 0.0469 AC: 1860 AN: 39674

South Asian (SAS) AF: 0.0763 AC: 6577 AN: 86190

European-Finnish (FIN) AF: 0.0654 AC: 3496 AN: 53416

Middle Eastern (MID) AF: 0.0512 AC: 295 AN: 5764

European-Non Finnish (NFE) AF: 0.0608 AC: 67593 AN: 1111498

Other (OTH) AF: 0.0550 AC: 3319 AN: 60362

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

African (AFR) AF: 0.0101 AC: 420 AN: 41582

American (AMR) AF: 0.0254 AC: 389 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0472 AC: 164 AN: 3472

East Asian (EAS) AF: 0.0312 AC: 162 AN: 5186

South Asian (SAS) AF: 0.0683 AC: 329 AN: 4818

European-Finnish (FIN) AF: 0.0817 AC: 866 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0574 AC: 3907 AN: 68022

Other (OTH) AF: 0.0350 AC: 74 AN: 2116

Alfa AF: 0.0517 Hom.: 306

Bravo AF: 0.0363

Asia WGS AF: 0.0430 AC: 150 AN: 3478

EpiCase AF: 0.0559

EpiControl AF: 0.0570

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	-0.51
CADD	Benign	8.5
DANN	Benign	0.78
PhyloP100		1.8
PromoterAI		0.021	Neutral
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)		0.010		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: rs9332801; hg19: chr11-118355642; COSMIC: COSV63283256; COSMIC: COSV63283256;