chr11-118436526-G-A

Variant names:

• chr11-118436526-G-A
• rs1336274284
• NM_001197104.2:c.14G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001197104.2(KMT2A):​c.14G>A​(p.Cys5Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000009 in 1,110,642 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C5S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.0e-7 (0 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.81
• Publications: 0 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

ENSG00000285827 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2	c.14G>A	p.Cys5Tyr	missense_variant	Exon 1 of 36	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8	c.14G>A	p.Cys5Tyr	missense_variant	Exon 1 of 36	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1	c.-798-32249G>A		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.00e-7 AC: 1 AN: 1110642 Hom.: 0 Cov.: 25 AF XY: 0.00000189 AC XY: 1 AN XY: 529374

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

African (AFR) AF: 0.00 AC: 0 AN: 23516

American (AMR) AF: 0.00 AC: 0 AN: 14546

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13586

East Asian (EAS) AF: 0.00 AC: 0 AN: 27780

South Asian (SAS) AF: 0.00 AC: 0 AN: 23328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3724

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 925696

Other (OTH) AF: 0.00 AC: 0 AN: 43270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	.;T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.76	T;T;T;T
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.90	L;L;.;L
PhyloP100		1.8
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-2.5	N;N;N;.
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Uncertain	0.010	D;D;D;.
Polyphen		0.94	.;P;P;.
Vest4		0.18
MutPred		0.42		Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);Gain of phosphorylation at C5 (P = 0.0398);
MVP		0.88
MPC		1.3
ClinPred		0.89	D
GERP RS		3.6
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.86
gMVP		0.54
Mutation Taster		=62/38	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: rs1336274284; hg19: chr11-118307241;