rs781973852

Variant names:

• chr11-118436590-C-A
• rs781973852
• NM_001197104.2:c.78C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-118436590-C-A
• chr11-118436590-C-G
• chr11-118436590-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_001197104.2(KMT2A):​c.78C>A​(p.Gly26Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000293 in 1,023,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: KMT2A NM_001197104.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0530
• Publications: 1 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

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 11-118436590-C-A is Benign according to our data. Variant chr11-118436590-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1555823.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.

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.78C>A	p.Gly26Gly	synonymous	Exon 1 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.78C>A	p.Gly26Gly	synonymous	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.78C>A	p.Gly26Gly	synonymous	Exon 1 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.78C>A	p.Gly26Gly	synonymous	Exon 1 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.78C>A	p.Gly26Gly	synonymous	Exon 1 of 36	ENSP00000374157.5	Q03164-1
	ENSG00000285827	ENST00000648261.1		c.-798-32185C>A		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000293 AC: 3 AN: 1023144 Hom.: 0 Cov.: 21 AF XY: 0.00000414 AC XY: 2 AN XY: 482870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000480 AC: 1 AN: 20840

American (AMR) AF: 0.00 AC: 0 AN: 6652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11914

East Asian (EAS) AF: 0.00 AC: 0 AN: 22118

South Asian (SAS) AF: 0.00 AC: 0 AN: 18850

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2774

European-Non Finnish (NFE) AF: 0.00000229 AC: 2 AN: 875236

Other (OTH) AF: 0.00 AC: 0 AN: 39426

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000102688), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.96
PhyloP100		-0.053
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Mutation Taster		=100/0	polymorphism

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: rs781973852; hg19: chr11-118307305;